Journal of Neurochemistry

"Cocaine Decreases Expression of Neurogranin via Alterations in Thyroid Receptor/Retinoid X Receptor Signaling"

Publication Date: 2012 Feb 2 PMID: 22300446
Authors: Kovalevich, J. - Corley, G. - Yen, W. - Kim, J. - Rawls, S. M. - Langford, D.
Journal: J Neurochem

Mounting evidence suggests a potential link between cocaine abuse, disruptions in hypothalamic-pituitary-thyroid (HPT) axis signaling, and neuroplasticity, but molecular mechanisms remain unknown. Neurogranin (Ng) is a gene containing a thyroid hormone responsive element (TRE) within its first intron that is involved in synaptic plasticity. Transcriptional activation requires heterodimerization of thyroid hormone receptor (TR) and retinoid X receptor (RXR) bound by their respective ligands, triiodothryonine (T3) and 9-cis-retinoic acid (9-cis RA), and subsequent binding of this complex to the TRE of the Ng gene. In this study, the effects of chronic cocaine abuse on Ng expression in euthyroid and hypothyroid mice were assessed. In cocaine-treated mice, decreased Ng expression was observed in the absence of changes in levels of thyroid hormones or other HPT signaling factors. Therefore, we hypothesized that cocaine decreases Ng expression via alterations in 9-cis-RA availability and TR/RXR signaling. In support of this hypothesis, RXR-gamma was significantly decreased in brains of cocaine-treated mice while CYP26A1, the main enzyme responsible for neuronal RA degradation, was significantly increased. Results from this study provide the first evidence for a direct effect of cocaine abuse on TR/RXR signaling, RA metabolism, and transcriptional regulation of Ng, a gene essential for adult neuroplasticity. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Sources Contributing to the Average Extracellular Concentration of Dopamine in the Nucleus Accumbens.

Publication Date: 2012 Feb 1 PMID: 22296263
Authors: Owesson-White, C. - Roitman, M. - Sombers, L. - Belle, A. - Keithley, R. - Peele, J. - Carelli, R. - Wightman, R.
Journal: J Neurochem

Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted dopamine levels in the NAc to establish a basal concentration. In this study we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in dopamine due to phasic firing - that is, the measurement of dopamine 'transients'. These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc. A series of experiments were designed to probe regulation of extracellular dopamine. Lidocaine was infused into the ventral tegmental area, the site of dopamine cell bodies, to arrest neuronal firing. While there was virtually no instantaneous change in dopamine concentration, longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level. Dopamine transporter (DAT) inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc. To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter (VMAT2) inhibitor, tetrabenazine, to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals. Tetrabenazine almost abolished phasic dopamine release but increased extracellular dopamine to approximately 500 nM, presumably by inducing reverse transport by DAT. Taken together, data presented here show that average extracellular dopamine in the NAc is low (20-30 nM) and largely arises from phasic dopamine transients. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Hypoxia regulation of ATP13A2 (PARK9) gene transcription.

Publication Date: 2012 Jan 31 PMID: 22288903
Authors: Xu, Q. - Guo, H. - Zhang, X. - Tang, B. - Cai, F. - Zhou, W. - Song, W.
Journal: J Neurochem

Parkinson's disease (PD) is the second most common neurodegenerative disorders with a variable combination of motor and non-motor symptoms. Mutations in several genes including ATP13A2 (PARK9) are reported to be associated with PD. The underlying mechanism of PD is not well defined, however, both genetic and environmental causes contribute to it. ATP13A2 gene locates in chromosome 1 and contains 29 exons encoding for a protein of 1180 amino acids with 10 transmembrane domains. Abnormal gene expression has been implicated in neurodegenerative disorders. The transcriptional regulation of the ATP13A2 gene is unknown. In this report we cloned and functionally characterized the human ATP13A2 gene promoter. We showed that the promoter region of the human ATP13A2 gene contains hypoxia response elements (HREs) which can bind to transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha). Hypoxia upregulated ATP13A2 transcription via HIF-1alpha in HEK293 and dopaminergic MN9D cells. Our study indicates that hypoxia signaling plays a very important role in the regulation of human ATP13A2 gene expression. Further study is needed to determine the role of hypoxia in the pathogenesis of PD and its interaction with other PD causative genes, which will provide insights to the role of hypoxia and dysregulation of gene expression in Parkinson's disease. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Cerebellins: capstones to bridge the synaptic cleft.

Publication Date: 2012 Jan 30 PMID: 22288876
Authors: Eiberger, B. - Schilling, K.
Journal: J Neurochem

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Sertraline inhibits presynaptic Na(+) channel mediated responses in hippocampus isolated nerve endings.

Publication Date: 2012 Jan 30 PMID: 22288826
Authors: Aldana, B. I. - Maria, S.
Journal: J Neurochem

In the present study a possible sertraline action on cerebral presynaptic Na(+) channels was investigated. For this purpose, the effect of sertraline on responses induced by the Na(+) channel opener, veratridine, namely the increase in Na(+) and in neurotransmitter release in hippocampus isolated nerve endings was investigated. Results show that sertraline in the low muM range (1.5 to 25 muM) progressively inhibits the rise in Na(+) and the release of preloaded [(3) H]Glu as well as the release of endogenous 5-HT, Glu and GABA (detected by HPLC) induced by veratridine depolarization either under external Ca(2+) -free conditions or in the presence of external Ca(2+) . In addition, under non depolarized conditions, sertraline (25 muM) increased the external concentration of 5-HT at expense of its internal concentration, and unchanged the external and internal concentrations of the amino acid neurotransmitters and of the 5-HT main metabolite, 5-HIAA. This result is consistent with the sertraline inhibitory action of the serotonin transporter. However, sertraline is unlikely to inhibit presynaptic Na(+) channels permeability by increasing external 5-HT. Because 5-HT in a wide concentration range (1 to1000 muM) did not change the veratridine-induced increase in Na(+) . In summary, present findings demonstrate that besides the inhibition of 5-HT reuptake, sertraline is an effective inhibitor of presynaptic Na(+) channels controlling neurotransmitter release. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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The vincamine derivative vindeburnol provides benefit in a mouse model of multiple sclerosis: Effects on the Locus coeruleus.

Publication Date: 2012 Jan 30 PMID: 22288774
Authors: Polak, P. E. - Kalinin, S. - Braun, D. - Sharp, A. - Lin, S. X. - Feinstein, D. L.
Journal: J Neurochem

The endogenous neurotransmitter noradrenaline (NA) plays several roles in maintaining brain homeostasis, including exerting anti-inflammatory and neuroprotective effects. The primary source of NA in the CNS are tyrosine hydroxylase (TH) positive neurons located in the Locus coeruleus (LC) which send projections throughout the brain and spinal cord. We recently demonstrated that dysregulation of the LC:Noradrenergic system occurs in experimental autoimmune encephalomyelitis (EAE) as well as in MS patients, associated with damage occurring to LC neurons. Vindeburnol, a structural analog of the cerebral vasodilator vincamine, was previously reported to increase TH expression and activity in LC neurons. Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide, and treated with vindeburnol at the first appearance of clinical signs. Clinical signs continued to increase for about 1 week, at which point mice in the vehicle group continued to worsen while vindeburnol treated mice showed improvement. Pro-inflammatory cytokine production from splenic T-cells was not reduced by vindeburnol suggesting primarily central actions of treatment. In the cerebellum, vindeburnol decreased astrocyte activation and reduced the number of demyelinated regions. Vindeburnol reduced astrocyte activation in the LC, reduced TH+ neuronal hypertrophy, increased expression of several genes involved in LC survival and maturation, and increased NA levels in the spinal cord. These results suggest that treatments with drugs such as vindeburnol which target LC survival or function could be of benefit in MS patients. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Hippocampal expression of myelin-associated inhibitors is induced with age-related cognitive decline and correlates with deficits of spatial learning and memory.

Publication Date: 2012 Jan 23 PMID: 22269040
Authors: Vanguilder, H. D. - Bixler, G. V. - Sonntag, W. E. - Freeman, W. M.
Journal: J Neurochem

Impairment of cognitive functions including hippocampus-dependent spatial learning and memory affects nearly half of the aged population. Age-related cognitive decline is associated with synaptic dysfunction that occurs in the absence of neuronal cell loss, suggesting that impaired neuronal signaling and plasticity may underlie age-related deficits of cognitive function. Expression of myelin-associated inhibitors (MAIs) of synaptic plasticity, including the ligands MAG, Nogo-A, and OMgp, and their common receptor, NgR1, was examined in hippocampal synaptosomes and CA1, CA3 and DG subregions derived from adult (12-13 months) and aged (26-28 months) Fischer 344 x Brown Norway rats. Rats were behaviorally phenotyped by Morris water maze testing and classified as aged cognitively intact (n=7-8) or aged cognitively impaired (n=7-10) relative to adults (n=5-7). MAI protein expression was induced in cognitively impaired, but not cognitively intact, aged rats and correlated with cognitive performance in individual rats. Immunohistochemical experiments demonstrated that upregulation of MAIs occurs, in part, in hippocampal neuronal axons and somata. While a number of pathways and processes are altered with brain aging, we report a coordinated induction of myelin-associated inhibitors of functional and structural plasticity only in cognitively impaired aged rats. Induction of MAIs may decrease stimulus-induced synaptic strengthening and structural remodeling, ultimately impairing synaptic mechanisms of spatial learning and memory and resulting in cognitive decline. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Ketone Bodies in Epilepsy.

Publication Date: 2012 Jan 23 PMID: 22268909
Authors: McNally, M. A. - Hartman, A. L.
Journal: J Neurochem

Seizures that are resistant to standard medications remain a major clinical problem. One underutilized option for patients with medication-resistant seizures is the high-fat, low-carbohydrate ketogenic diet. The diet received its name based on the observation that patients consuming this diet produce ketone bodies (e.g., acetoacetate, beta-hydroxybutyrate, and acetone). Although the exact mechanisms of the diet are unknown, ketone bodies have been hypothesized to contribute to the anticonvulsant and antiepileptic effects. In this review, anticonvulsant properties of ketone bodies and the ketogenic diet are discussed (including GABAergic and glutamatergic effects). Because of the importance of ketone body metabolism in the early stages of life, the effects of ketone bodies on developing neurons in vitro also are discussed. Understanding how ketone bodies exert their effects will help optimize their use in treating epilepsy and other neurological disorders. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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CORRIGENDUM.

Publication Date: 2012 Jan 23 PMID: 22268849
Authors:
Journal: J Neurochem

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Mark A. Smith: neurocytochemistry innovator.

Publication Date: 2012 Jan 23 PMID: 22268813
Authors: Zhu, X. - Castellani, R. J. - Ziats, N. P. - Petersen, R. B. - Gon Lee, H. - Perry, G.
Journal: J Neurochem

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Ammonia Increases Paracellular Permeability of Rat Brain Endothelial Cells by a Mechanism Encompassing Oxidative/Nitrosative Stress and Activation of Matrix Metalloproteinases.

Publication Date: 2012 Jan 19 PMID: 22260250
Authors: Skowronska, M. - Zielinska, M. - Wojcik-Stanaszek, L. - Ruszkiewicz, J. - Milatovic, D. - Aschner, M. - Albrecht, J.
Journal: J Neurochem

Ammonia is responsible for cerebral edema (CE) associated with acute liver failure (ALF), but the role of the vasogenic mechanism has been a matter of dispute. Here, we tested the hypothesis that ammonia induces changes in blood-brain barrier (BBB) permeability by a mechanism coupled to oxidative/ nitrosative stress (ONS) evoked in the BBB-forming cerebral capillary endothelial cells. Treatment of a rat brain endothelial cell line (RBE-4) with ammonia (5 mmol/L, 24h) caused accumulation of ONS markers: reactive oxygen species (ROS), nitric oxide (NO) and peroxidation products of phospholipid-bound arachidonic acid, F2-isoprostanes (F2-IsoPs). Concurrently, ammonia increased the activity of extracellular matrix metalloproteinases (MMP-2/ MMP-9), increased cell permeability to fluorescein isothiocyanate (FITC)-dextran (40 kDa), and increased the expression of y+LAT2, a transporter that mediates the uptake to the cells of the NO precursor, arginine (Arg). The increase of cell permeability was ameliorated upon co-treatment with a MMP inhibitor, SB-3CT and with an antioxidant, glutathione diethyl ester (GEE), which also reduced F2-IsoPs. Ammonia-induced ONS was attenuated by cytoprotective agents L- ornithine (Orn), phenylbutyrate (PB), and their conjugate L-ornithine phenylbutyrate (OP), an ammonia-trapping drug used to treat hyperammonemia. The results support the concept that ONS and ONS-related activation of MMPs in cerebral capillary endothelial cells contribute to the alterations in BBB permeability and to the vasogenic component of CE associated with ALF. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Brain insulin resistance accelerates Ass fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes.

Publication Date: 2012 Jan 19 PMID: 22260232
Authors: Yamamoto, N. - Matsubara, T. - Sobue, K. - Tanida, M. - Kasahara, R. - Naruse, K. - Taniura, H. - Sato, T. - Suzuki, K.
Journal: J Neurochem

Type 2 diabetes mellitus is thought to be a significant risk factor for Alzheimer's disease. Insulin resistance also affects the CNS by regulating key processes, such as neuronal survival and longevity, learning and memory. However, the mechanisms underlying these effects remain uncertain. To investigate whether insulin resistance is associated with the assembly of amyloid ss-protein at the cell surface of neurons, we inhibited insulin-signalling pathways of primary neurons. The treatments of insulin receptor (IR)-knockdown and a phosphatidylinositol 3-kinase inhibitor (LY294002), but not an extracellular signal-regulated kinase inhibitor, induced an increase in GM1 ganglioside levels in detergent-resistant membrane microdomains of the neurons. The aged db/db mouse brain exhibited reduction of IR expression and phosphorylation of Akt, which later induced an increase of the high-density GM1 ganglioside-clusters on synaptosomes. Neurons treated with IR knockdown or LY294002, and synaptosomes of the aged db/db mouse brains markedly accelerated an assembly of amyloid ss proteins. These results suggest that ageing and peripheral insulin resistance induce brain insulin resistance, which accelerate the assembly of amyloid ss proteins by increasing and clustering of GM1 gangliosides in detergent-resistant membrane microdomains of neuronal membranes. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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The T-type voltage-gated calcium channel as a molecular target of the novel cognitive enhancer ST101: Enhancement of long-term potentiation and CaMKII autophosphorylation in rat cortical slices.

Publication Date: 2012 Jan 17 PMID: 22251222
Authors: Moriguchi, S. - Shioda, N. - Yamamoto, Y. - Tagashira, H. - Fukunaga, K.
Journal: J Neurochem

Here we report that ST101 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one; previously coded as ZSET1446) targets T-type voltage-gated calcium channels in mediating improved cognition in the central nervous system. We prepared rat somatosensory cortical and hippocampal slices, treated them with 0.01 to 100 nM ST101, and performed immunoblotting and electrophysiological analyses using various voltage-gated calcium channel (VGCC) inhibitors. Treatment of rat cortical slices with a range of ST101 concentrations significantly increased CaMKII autophosphorylation following a bell-shaped dose-response curve, with 0.1 nM ST101 representing the maximally effective concentration. PKCalpha autophosphorylation was also significantly increased by 0.1 nM ST101 treatment. ST101 treatment had a moderate effect on CaMKII autophosphorylation but no effect on hippocampal PKCalpha autophosphorylation in slice preparations. Consistent with increased cortical CaMKII autophosphorylation, GluR1 (Ser-831) phosphorylation as a CaMKII postsynaptic substrate was significantly increased by treatment with 0.1 to 1 nM ST101, whereas phosphorylation of the presynaptic substrate synapsin I (Ser-603) remained unchanged. Notably, enhanced CaMKII autophosphorylation seen following 0.1 nM ST101 treatment was significantly inhibited by pretreatment with 1 muM mibefradil, a T-type VGCC inhibitor, but not with N-type (omega-conotoxin), P/Q-type (omega-agatoxin) or L-type (nifedipine) varsigmaG ChiChi inhibitors. Similarly, 0.1 nM ST101 significantly potentiated long-term potentiation (LTP) in cortical but not hippocampal slices. Enhanced LTP in cortical slices was totally inhibited by 1 muM mibefadil treatment. Finally, whole-cell patch-clamp analysis of Neuro2A cells overexpressing recombinant human Ca(V) 3.1 (alpha1G) T-channels and treated with 0.1 nM ST101 showed significant increases in T-type VGCC currents. These results indicate that T-type VGCCs are direct molecular targets for the novel cognitive enhancer ST101, a potential Alzheimer disease therapeutic. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor.

Publication Date: 2012 Jan 17 PMID: 22251169
Authors: Yang, Z. J. - Carter, E. L. - Kibler, K. K. - Kwansa, H. - Crafa, D. A. - Martin, L. J. - Roman, R. J. - Harder, D. R. - Koehler, R. C.
Journal: J Neurochem

J. Neurochem. (2012) 10.1111/j.1471-4159.2012.07666.x ABSTRACT: 20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 metabolite of arachidonic acid that that contributes to infarct size following focal cerebral ischemia. However, little is known about the role of 20-HETE in global cerebral ischemia or neonatal hypoxia-ischemia (H-I). The present study examined the effects of blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) in neonatal piglets after H-I to determine if it protects highly vulnerable striatal neurons. Administration of HET0016 after H-I improved early neurological recovery and protected neurons in putamen after 4 days of recovery. HET0016 had no significant effect on cerebral blood flow. cytochrome P450 4A immunoreactivity was detected in putamen neurons, and direct infusion of 20-HETE in the putamen increased phosphorylation of Na(+) ,K(+) -ATPase and NMDA receptor NR1 subunit selectively at protein kinase C-sensitive sites but not at protein kinase A-sensitive sites. HET0016 selectively inhibited the H-I induced phosphorylation at these same sites at 3 h of recovery and improved Na(+) ,K(+) -ATPase activity. At 3 h, HET0016 also suppressed H-I induced extracellular signal-regulated kinase 1/2 activation and protein markers of nitrosative and oxidative stress. Thus, 20-HETE can exert direct effects on key proteins involved in neuronal excitotoxicity in vivo and contributes to neurodegeneration after global cerebral ischemia in immature brain.

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Kainate receptor-mediated depression of glutamatergic transmission involving protein kinase A in the lateral amygdala.

Publication Date: 2012 Jan 17 PMID: 22251150
Authors: Negrete-Diaz, J. V. - Duque-Feria, P. - Andrade-Talavera, Y. - Carrion, M. - Flores, G. - Rodriguez-Moreno, A.
Journal: J Neurochem

J. Neurochem. (2012) 10.1111/j.1471-4159.2012.07665.x ABSTRACT: Kainate receptors (KARs) have been described as modulators of synaptic transmission at different synapses. However, this role of KARs has not been well characterized in the amygdala. We have explored the effect of kainate receptor activation at the synapse established between fibers originating at medial geniculate nucleus and the principal cells in the lateral amygdala. We have observed an inhibition of evoked excitatory postsynaptic currents (eEPSCs) amplitude after a brief application of KARs agonists KA and ATPA. Paired-pulse recordings showed a clear pair pulse facilitation that was enhanced after KA or ATPA application. When postsynaptic cells were loaded with BAPTA, the depression of eEPSC amplitude observed after the perfusion of KAR agonists was not prevented. We have also observed that the inhibition of the eEPSCs by KARs agonists was prevented by protein kinase A but not by protein kinase C inhibitors. Taken together our results indicate that KARs present at this synapse are pre-synaptic and their activation mediate the inhibition of glutamate release through a mechanism that involves the activation of protein kinase A.

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Glial cells in (patho)physiology.

Publication Date: 2012 Jan 17 PMID: 22251135
Authors: Parpura, V. - Heneka, M. T. - Montana, V. - Oliet, S. H. - Schousboe, A. - Haydon, P. G. - Stout, R. F. Jr - Spray, D. C. - Reichenbach, A. - Pannicke, T. - Pekny, M. - Pekna, M. - Zorec, R. - Verkhratsky, A.
Journal: J Neurochem

J. Neurochem. (2012) 10.1111/j.1471-4159.2012.07664.x ABSTRACT: Neuroglial cells define brain homeostasis and mount defense against pathological insults. Astroglia regulate neurogenesis and development of brain circuits. In the adult brain, astrocytes enter into intimate dynamic relationship with neurons, especially at synaptic sites where they functionally form the tripartite synapse. At these sites, astrocytes regulate ion and neurotransmitter homeostasis, metabolically support neurons and monitor synaptic activity; one of the readouts of the latter manifests in astrocytic intracellular Ca(2+) signals. This form of astrocytic excitability can lead to release of chemical transmitters via Ca(2+) -dependent exocytosis. Once in the extracellular space, gliotransmitters can modulate synaptic plasticity and cause changes in behavior. Besides these physiological tasks, astrocytes are fundamental for progression and outcome of neurological diseases. In Alzheimer's disease, for example, astrocytes may contribute to the etiology of this disorder. Highly lethal glial-derived tumors use signaling trickery to coerce normal brain cells to assist tumor invasiveness. This review not only sheds new light on the brain operation in health and disease, but also points to many unknowns.

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Synergistic inhibitory effect of nicotine plus oral contraceptive on mitochondrial complex-IV is mediated by estrogen receptor-beta in female rats.

Publication Date: 2012 Jan 16 PMID: 22248091
Authors: Raval, A. P. - Dave, K. R. - Saul, I. - Gonzalez, G. J. - Diaz, F.
Journal: J Neurochem

Chronic nicotine and oral contraceptive (NOC) exposure caused significant loss of hippocampal membrane-bound estrogen receptor-beta (ER-beta) in female rats compared with exposure to nicotine alone. Mitochondrial ER-beta regulates estrogen-mediated mitochondrial structure and function; therefore, investigating the impact of NOC on mitochondrial ER-beta and its function could help delineate the harmful synergism between nicotine and OC. In the current study, we tested the hypothesis that NOC-induced loss of mitochondrial ER-beta alters the oxidative phosphorylation system protein levels and mitochondrial respiratory function. This hypothesis was tested in hippocampal mitochondria isolated from female rats exposed to saline, nicotine, OC or NOC for 16 days. NOC decreased the mitochondrial ER-beta protein levels and reduced oxygen consumption and complex IV (CIV) activity by 34% and 26% compared to saline- or nicotine-administered groups, respectively. We also observed significantly low protein levels of all mitochondrial-encoded CIV subunits after NOC as compared to the nicotine or saline groups. Similarly, the silencing of ER-beta reduced the phosphorylation of cyclic-AMP response element binding protein, and also reduced levels of CIV mitochondrial-encoded subunits after estrogen stimulation. Overall, these results suggest that mitochondrial ER-beta loss is responsible for mitochondrial malfunction after NOC. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Saturated Long Chain Fatty acids Activate Inflammatory Signaling in Astrocytes.

Publication Date: 2012 Jan 16 PMID: 22248073
Authors: Gupta, S. - Knight, A. G. - Gupta, S. - Keller, J. N. - Bruce-Keller, A. J.
Journal: J Neurochem

This study describes the effects of long-chain fatty acids on inflammatory signaling in cultured astrocytes. Data show that the saturated fatty acid palmitic acid, as well as lauric acid and stearic acid, trigger the release of TNFalpha and IL-6 from astrocytes. Unsaturated fatty acids were unable to induce cytokine release from cultured astrocytes. Furthermore, the effects of palmitic acid on cytokine release require TLR4 rather than CD36 or TLR2, and do not depend on palmitic acid metabolism to palmitoyl-CoA. Inhibitor studies revealed that pharmacologic inhibition of p38 or p42/44 MAPK pathways prevents the pro-inflammatory effects of palmitic acid, while JNK and PI3K inhibition does not affect cytokine release. Depletion of microglia from primary astrocyte cultures using the lysosomotropic agent l-Leucine methyl ester (LME) revealed that the ability of palmitic acid to trigger cytokine release is not dependent on the presence of microglia. Finally, data show that the essential omega-3 fatty acid docosahexaenoic acid (DHA) acts in a dose-dependent manner to prevent the actions of palmitic acid on inflammatory signaling in astrocytes. Collectively, these data demonstrate the ability of saturated fatty acids to induce astrocyte inflammation in vitro. These data thus raise the possibility that high levels of circulating saturated fatty acids could cause reactive gliosis and brain inflammation in vivo, and could potentially participate in the reported adverse neurologic consequences of obesity and metabolic syndrome. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Microglial neurotransmitter receptors trigger superoxide production in microglia; consequences for microglial-neuronal interactions.

Publication Date: 2012 Jan 13 PMID: 22243365
Authors: Mead, E. L. - Mosley, A. - Eaton, S. - Dobson, L. - Heales, S. J. - Pocock, J. M.
Journal: J Neurochem

Microglia express three isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Nox1, Nox2 and Nox4, with the potential to produce superoxide (O(2) (.-) ). Microglia also express neurotransmitter receptors, which can modulate microglial responses. Here microglial activity of Nox1, Nox2 and Nox4 in primary rat cultured microglia or the rodent BV2 cell line were altered by microglial neurotransmitter receptor modulation. Glutamate, GABA or ATP triggered microglial O(2) (.-) production via Nox activation. Nox activation was elicited by agonists of metabotropic mGlu3 receptors and by group III receptors, by GABA(A) but not GABA(B) receptors, and by purinergic P2X(7) or P2Y(2/4) receptors but not P2Y(1) receptors, and inhibited by mGluR5 antagonists. The neurotransmitters also modulated Nox mRNA expression and NADPH activity. The activation of Nox by BzATP or GABA promoted a neuroprotective phenotype whilst the activation of Nox by glutamate promoted a neurotoxic phenotype. Taken together, these data indicate that microglial neurotransmitter receptors can signal via Nox to promote neuroprotection or neurotoxicity. This has implications for the subsequent neurotoxic profile of microglia when neurotransmitter levels may become skewed in neurodegeneration. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Activated Leukocyte Cell Adhesion Molecule (Alcam) Modulates Neurotrophin Signaling.

Publication Date: 2012 Jan 13 PMID: 22243278
Authors: Wade, A. - Thomas, C. - Kalmar, B. - Terenzio, M. - Garin, J. - Greensmith, L. - Schiavo, G.
Journal: J Neurochem

Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) have been shown to modulate growth factor signaling and follow complex trafficking pathways in neurons. Similarly, several growth factors, including members of the neurotrophin family, undergo axonal retrograde transport that is required to elicit their full signaling potential in neurons. We sought to determine whether IgCAMs that enter the axonal retrograde transport route co-operate with neurotrophin signaling. We identified Activated Leukocyte Cell Adhesion Molecule (ALCAM), a protein involved in axon pathfinding and development of the neuromuscular junction, to be associated with an axonal endocytic compartment that contains neurotrophins and their receptors. Although ALCAM enters carriers that are transported bidirectionally in motor neuron axons, it is predominantly co-transported with the neurotrophin receptor p75(NTR) toward the cell body. ALCAM was found to specifically potentiate Nerve Growth Factor (NGF)-induced differentiation and signaling. The extracellular domain of ALCAM is both necessary and sufficient to potentiate NGF-induced neurite outgrowth, and its homodimerization is required for this novel role. Our findings indicate that ALCAM synergizes with NGF to induce neuronal differentiation, raising the possibility that it functions not only as an adhesion molecule but also in the modulation of growth factor signaling in the nervous system. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.

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Minimal essential length of Clostridium botulinum C3 peptides to enhance neuronal regenerative growth and connectivity in a non-enzymatic mode.

Publication Date: 2012 Jan 12 PMID: 22239108
Authors: Loske, P. - Boato, F. - Hendrix, S. - Piepgras, J. - Just, I. - Ahnert-Hilger, G. - Holtje, M.
Journal: J Neurochem

C3 ADP-ribosyltransferase is a valuable tool to study Rho-dependent cellular processes. In the current study we investigated the impact of enzyme-deficient peptides derived from Clostridium botulinum C3 transferase in the context of neuronal process elongation and branching, synaptic connectivity, and putative beneficial effects on functional outcome following traumatic injury to the CNS. By screening a range of peptidic fragments we identified three short peptides from C3bot that promoted axon and dendrite outgrowth in cultivated hippocampal neurons. Furthermore, one of these fragments, a 26-amino acid peptide covering the residues 156-181 enhanced synaptic connectivity in primary hippocampal culture. This peptide was also effective to foster axon outgrowth and re-innervation in organotypical brain slice culture. To evaluate the potential of the 26mer to foster repair mechanisms after CNS injury we applied this peptide to mice subjected to spinal cord injury by either compression impact or hemisection. A single local administration at the site of the lesion improved locomotor recovery. In addition, histological analysis revealed an increased serotonergic input to lumbar motoneurons in treated compared to control mice. Pull-down assays showed that lesion-induced up-regulation of RhoA activity within the spinal cord was largely blocked by C3bot peptides despite the lack of enzymatic activity. (c) 2012 The Authors Journal of Neurochemistry(c) 2012 International Society for Neurochemistry.

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A role for neuroserpin in neuron morphological development.

Publication Date: 2012 Jan 10 PMID: 22233399
Authors: Man, H. Y. - Ma, X. M.
Journal: J Neurochem

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An astrocyte-specific enhancer of the aquaporin-4 gene functions through a consensus sequence of POU transcription factors in concert with multiple upstream elements.

Publication Date: 2012 Jan 7 PMID: 22225570
Authors: Abe, Y. - Ikeshima-Kataoka, H. - Goda, W. - Niikura, T. - Yasui, M.
Journal: J Neurochem

J. Neurochem. (2012) 10.1111/j.1471-4159.2012.07652.x ABSTRACT: Aquaporin-4, a predominant water channel in the brain, is specifically expressed in astrocyte endfeet and plays a central role in water homeostasis, neuronal activity, and cell migration in the brain. It has two dominant isoforms called M1 and M23, whose mRNA is driven by distinct promoters located upstream of exons 0 and 1 of the aquaporin-4 gene, respectively. To identify cis-acting elements responsible for the astrocyte-specific transcription of M1 mRNA, the promoter activity of the 5'-flanking region upstream of exon 0 in primary cultured mouse astrocytes was examined by luciferase assay, and sequences, where nuclear factors bind, were identified by electrophoretic mobility shift assay. An astrocyte-specific activity enhancing transcription from the M1 promoter was observed within approximately 2 kb from the transcriptional start sites of M1 mRNA. At least five elements clustered within the 286-bp region were found to function as a novel astrocyte-specific enhancer. Among the five elements, a consensus sequence of Pit-1/Oct/Unc-86 (POU) transcription factors was indispensable to the astrocyte-specific enhancer since disruption of the POU motif completely abolished the enhancer activity in astrocytes. However, the POU motif alone had little activity, indicating the requirement for cooperation with other upstream elements to exert full enhancer activity.

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Editorial Highlight: New insights on regulation of LMTK2, a membrane kinase integrating pathways central to neurodegeneration.

Publication Date: 2012 Jan 7 PMID: 22224437
Authors: Rattray, M.
Journal: J Neurochem

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Enzymatic transamination of d-kynurenine generates kynurenic acid in rat and human brain.

Publication Date: 2012 Jan 7 PMID: 22224417
Authors: Perez-de la Cruz, V. - Amori, L. - Sathyasaikumar, K. V. - Wang, X. D. - Notarangelo, F. M. - Wu, H. Q. - Schwarcz, R.
Journal: J Neurochem

J. Neurochem. (2012) 10.1111/j.1471-4159.2012.07653.x ABSTRACT: In the mammalian brain, the alpha7 nicotinic and NMDA receptor antagonist kynurenic acid is synthesized by irreversible enzymatic transamination of the tryptophan metabolite l-kynurenine. d-kynurenine, too, serves as a bioprecursor of kynurenic acid in several organs including the brain, but the conversion is reportedly catalyzed through oxidative deamination by d-aminoacid oxidase. Using brain and liver tissue homogenates from rats and humans, and conventional incubation conditions for kynurenine aminotransferases, we show here that kynurenic acid production from d-kynurenine, like the more efficient kynurenic acid synthesis from l-kynurenine, is blocked by the aminotransferase inhibitor amino-oxyacetic acid. In vivo, focal application of 100 muM d-kynurenine by reverse microdialysis led to a steady rise in extracellular kynurenic acid in the rat striatum, causing a 4-fold elevation after 2 h. Attesting to functional significance, this increase was accompanied by a 36% reduction in extracellular dopamine. Both of these effects were duplicated by perfusion of 2 muM l-kynurenine. Co-infusion of amino-oxyacetic acid (2 mM) significantly attenuated the in vivo effects of d-kynurenine and essentially eliminated the effects of l-kynurenine. Thus, enzymatic transamination accounts in part for kynurenic acid synthesis from d-kynurenine in the brain. These results are discussed with regard to implications for brain physiology and pathology.

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Group IVA Phospholipase A(2) is Necessary for Growth Cone Repulsion and Collapse.

Publication Date: 2012 Jan 5 PMID: 22220903
Authors: Sanford, S. D. - Yun, B. G. - Leslie, C. C. - Murphy, R. C. - Pfenninger, K. H.
Journal: J Neurochem

The repellent semaphorin 3A (Sema3A) causes growth cone turning or collapse by triggering cytoskeletal rearrangements and detachment of adhesion sites. Growth cone detachment is dependent on eicosanoid activation of protein kinase C epsilon (PKCepsilon), but the characterization of the phospholipase A(2) (PLA(2) ) that releases arachidonic acid (AA) for eicosanoid synthesis has remained elusive. Here we show in rat dorsal root ganglion neurons that Sema3A stimulates PLA(2) activity, that Sema3A-induced growth cone turning and collapse are dependent on the release of AA, and that the primary PLA(2) involved is the Group IV alpha isoform (GIVA). Silencing GIVA expression renders growth cones resistant to Sema3A-induced collapse, and GIVA inhibition reverses Sema3A-induced repulsion into attraction. These studies identify a novel, early step in Sema3A-signaling and a PLA(2) necessary for growth cone repulsion and collapse. (c) 2012 The Authors Journal of Neurochemistry(c) 2012 International Society for Neurochemistry.

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Cdk5/p35 phosphorylates lemur tyrosine kinase-2 to regulate protein phosphatase-1C phosphorylation and activity.

Publication Date: 2012 Jan 5 PMID: 22220831
Authors: Manser, C. - Vagnoni, A. - Guillot, F. - Davies, J. - Miller, C. C.
Journal: J Neurochem

Cyclin dependent kinase-5 (cdk5)/p35 and protein phosphatase-1 (PP1) are two major enzymes that control a variety of physiological processes within the nervous system including neuronal differentiation, synaptic plasticity and axonal transport. Defective cdk5/p35 and PP1 function are also implicated in several major human neurodegenerative diseases. Cdk5/p35 and the catalytic subunit of PP1 (PP1C) both bind to the brain enriched, serine-threonine kinase lemur tyrosine kinase-2 (LMTK2). Moreover, LMTK2 phosphorylates PP1C on threonine-320 (PP1Cthr(320) ) to inhibit its activity. Here we demonstrate that LMTK2 is phosphorylated on serine-1418 (LMTK2ser(1418) ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate PP1Cthr(320) . We thus describe a new signalling pathway within the nervous system that links cdk5/p35 with PP1C and which has implications for a number of neuronal functions and neuronal dysfunction. (c) 2012 The Authors Journal of Neurochemistry(c) 2012 International Society for Neurochemistry.

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Epigenetic dysregulation of the dopamine system in diet-induced obesity.

Publication Date: 2012 Jan 5 PMID: 22220805
Authors: Vucetic, Z. - Carlin, J. - Totoki, K. - Reyes, T. M.
Journal: J Neurochem

Chronic intake of high fat diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to high fat diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry (ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC)), critical for coding the rewarding properties of palatable food and important in hedonically-driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in expression in dopamine-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased versus decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT) and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking chronic intake of high fat diet with altered dopamine-related gene expression, and this response varies by brain region and DNA sequence. (c) 2012 The Authors Journal of Neurochemistry(c) 2012 International Society for Neurochemistry.

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The Cbln Family of Proteins Interact with Multiple Signaling Pathways.

Publication Date: 2012 Jan 5 PMID: 22220752
Authors: Wei, P. - Pattarini, R. - Rong, Y. - Guo, H. - Bansal, P. K. - Kusnoor, S. V. - Deutch, A. Y. - Parris, J. - Morgan, J. I.
Journal: J Neurochem

Cbln1 is essential for synapse integrity in cerebellum through assembly into complexes that bridge presynaptic beta-neurexins (Nrxn) to postsynaptic GluRdelta2. However, GluRdelta2 is largely cerebellum-specific, yet Cbln1 and its little studied family members, Cbln2 and Cbln4, are expressed throughout brain. Therefore, we investigated whether additional proteins mediate Cbln family actions. Whereas Cbln1 and Cbln2 bound to GluRdelta2 and Nrxns1-3, Cbln4 bound weakly or not at all, suggesting it has distinct binding partners. In a candidate receptor-screening assay, Cbln4 (but not Cbln1 or Cbln2) bound selectively to the netrin receptor, DCC (deleted in colorectal cancer) in a netrin-displaceable fashion. To determine whether Cbln4 had a netrin-like function, Cbln4-null mice were generated. Cbln4-null mice did not phenocopy netrin-null mice. Cbln1 and Cbln4 were likely co-localized in neurons thought to be responsible for synaptic changes in striatum of Cbln1-null mice. Furthermore, complexes containing Cbln1 and Cbln4 had greatly reduced affinity to DCC but increased affinity to Nrxns, suggesting a functional interaction. However, Cbln4-null mice lacked the striatal synaptic changes seen in Cbln1-null mice. Thus Cbln family members interact with multiple receptors/signaling pathways in a subunit composition-dependent manner and have independent functions with Cbln4 potentially involved in the less-well characterized role of netrin/DCC in adult brain. (c) 2012 The Authors Journal of Neurochemistry(c) 2012 International Society for Neurochemistry.

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Retinal cone and rod photoreceptor cells exhibit differential susceptibility to light-induced damage.

Publication Date: 2012 Jan 5 PMID: 22220722
Authors: Okano, K. - Maeda, A. - Chen, Y. - Chauhan, V. - Tang, J. - Palczewska, G. - Sakai, T. - Tsuneoka, H. - Palczewski, K. - Maeda, T.
Journal: J Neurochem

All-trans-retinal and its condensation-products can cause retinal degeneration in a light-dependent manner and contribute to the pathogenesis of human macular diseases such as Stargardt's disease and age-related macular degeneration (AMD). Although these toxic retinoid by-products originate from rod and cone photoreceptor cells, the contribution of each cell type to light-induced retinal degeneration is unknown. Here the primary objective was to learn whether rods or cones are more susceptible to light-induced, all-trans-retinal-mediated damage. Previously, we reported that mice lacking enzymes that clear all-trans-retinal from the retina, ATP-binding cassette transporter 4 (ABCA4) and retinol dehydrogenase 8 (RDH8), manifested light-induced retinal dystrophy. We first examined early-stage-AMD patients and found retinal degenerative changes in rod-rich rather than cone-rich regions of the macula. We then evaluated transgenic mice with rod-only and cone-like-only retinas in addition to progenies of such mice inbred with Rdh8(-/-) Abca4(-/-) mice. Of all these strains, Rdh8(-/-) Abca4(-/-) mice with a mixed rod-cone population showed the most severe retinal degeneration under regular cyclic light conditions. Intense light exposure induced acute retinal damage in Rdh8(-/-) Abca4(-/-) and rod-only mice but not cone-like-only mice. These findings suggest that progression of retinal degeneration in Rdh8(-/-) Abca4(-/-) mice is affected by differential vulnerability of rods and cones to light. (c) 2012 The Authors Journal of Neurochemistry(c) 2012 International Society for Neurochemistry.

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Serine Hydroxymethyltransferase 1 and 2: Gene Sequence Variation and Functional Genomic Characterization.

Publication Date: 2012 Jan 5 PMID: 22220685
Authors: Hebbring, S. J. - Chai, Y. - Ji, Y. - Abo, R. P. - Jenkins, G. D. - Fridley, B. - Zhang, J. - Eckloff, B. W. - Wieben, E. D. - Weinshilboum, R. M.
Journal: J Neurochem

Serine hydroxymethyltransferase (SHMT) catalyzes the transfer of a beta carbon from serine to tetrahydrofolate (THF) to form glycine and 5,10-methylene-THF. This reaction plays an important role in neurotransmitter synthesis and metabolism. We set out to resequence SHMT1 and SHMT2, followed by functional genomic studies. We identified 87 and 60 polymorphisms in SHMT1 and SHMT2, respectively. We observed no significant functional effect of the 13 nonsynonymous SNPs in these genes, either on catalytic activity or protein quantity. We imputed additional variants across the two genes using "1000 Genomes" data, and identified 14 variants that were significantly associated (p-value < 1.0E-10) with SHMT1 mRNA expression in lymphoblastoid cell lines. Many of these SNPs were also significantly correlated with basal SHMT1 protein expression in 268 human liver biopsy samples. Reporter gene assays suggested that the SHMT1 promoter SNP, rs669340, contributed to this variation. Finally, SHMT1 and SHMT2 expression were significantly correlated with those of other Folate and Methionine Cycle genes at both the mRNA and protein levels. These experiments represent a comprehensive study of SHMT1 and SHMT2 gene sequence variation and its functional implications. In addition, we obtained preliminary indications that these genes may be co-regulated with other Folate and Methionine Cycle genes. (c) 2012 The Authors Journal of Neurochemistry(c) 2012 International Society for Neurochemistry.

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A specific multi-nutrient formulation enhances M1 muscarinic acetylcholine receptor responses in vitro.

Publication Date: 2012 Feb PMID: 22146060
Authors: Savelkoul, P. J. - Janickova, H. - Kuipers, A. A. - Hageman, R. J. - Kamphuis, P. J. - Dolezal, V. - Broersen, L. M.
Journal: J Neurochem

J. Neurochem. (2012) 120, 631-640. ABSTRACT: Recent evidence indicates that supplementation with a specific combination of nutrients may affect cell membrane synthesis and composition. To investigate whether such nutrients may also modify the physical properties of membranes, and affect membrane-bound processes involved in signal transduction pathways, we studied the effects of nutrient supplementation on G protein-coupled receptor activation in vitro. In particular, we investigated muscarinic receptors, which are important for the progression of memory deterioration and pathology of Alzheimer's disease. Nerve growth factor differentiated pheochromocytoma cells that were supplemented with specific combinations of nutrients showed enhanced responses to muscarinic receptor agonists in a membrane potential assay. The largest effects were obtained with a combination of nutrients known as Fortasyn Connect, comprising docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate as a uridine source, choline, vitamin B6, vitamin B12, folic acid, phospholipids, vitamin C, vitamin E, and selenium. In subsequent experiments, it was shown that the effects of supplementation could not be attributed to single nutrients. In addition, it was shown that the agonist-induced response and the supplement-induced enhancement of the response were blocked with the muscarinic receptor antagonists atropine, telenzepine, and AF-DX 384. In order to determine whether the effects of Fortasyn Connect supplementation were receptor subtype specific, we investigated binding properties and activation of human muscarinic M1, M2 and M4 receptors in stably transfected Chinese hamster ovary cells after supplementation. Multi-nutrient supplementation did not change M1 receptor density in plasma membranes. However, M1 receptor-mediated G protein activation was significantly enhanced. In contrast, supplementation of M2- or M4-expressing cells did not affect receptor signaling. Taken together, these results indicate that a specific combination of nutrients acts synergistically in enhancing muscarinic M1 receptor responses, probably by facilitating receptor-mediated G protein activation.

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Modulation of glutamate release from parallel fibers by mGlu4 and pre-synaptic GABA(A) receptors.

Publication Date: 2012 Feb PMID: 22145864
Authors: Antflick, J. E. - Hampson, D. R.
Journal: J Neurochem

J. Neurochem. (2012) 120, 552-563. ABSTRACT: The regulation of pre-synaptic glutamate release is important in the maintenance and fidelity of excitatory transmission in the nervous system. In this study, we report a novel interaction between a ligand-gated ion channel and a G-protein coupled receptor which regulates glutamate release from parallel fiber axon terminals. Immunocytochemical analysis revealed that GABA(A) receptors and the high affinity group III metabotropic glutamate receptor subtype 4 (mGlu4) are co-localized on glutamatergic parallel fiber axon terminals in the cerebellum. GABA(A) and mGlu4 receptors were also found to co-immunoprecipitate from cerebellar membranes. Independently, these two receptors have opposing roles on glutamate release: pre-synaptic GABA(A) receptors promote, while mGlu4 receptors inhibit, glutamate release. However, coincident activation of GABA(A) receptors with muscimol and mGlu4 with the agonist (2S)-S-2-amino-4-phosphonobutanoic acid , increased glutamate release from [(3) H]glutamate-loaded cerebellar synaptosomes above that observed with muscimol alone. Further support for an interaction between GABA(A) and mGlu4 receptors was obtained in the mGlu4 knockout mouse which displayed reduced binding of the GABA(A) ligand [(35) S]tert-butylbicyclophosphorothionate, and decreased expression of the alpha1, alpha6, beta2 GABA(A) receptor subunits in the cerebellum. Taken together, our data suggest a new role for mGlu4 whereby simultaneous activation with GABA(A) receptors acts to amplify glutamate release at parallel fiber-Purkinje cell synapses.

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Reduced calcium/calmodulin-dependent protein kinase II activity in the hippocampus is associated with impaired cognitive function in MPTP-treated mice.

Publication Date: 2012 Feb PMID: 22136399
Authors: Moriguchi, S. - Yabuki, Y. - Fukunaga, K.
Journal: J Neurochem

J. Neurochem. (2012) 120, 541-551. ABSTRACT: Parkinson's disease (PD) patients frequently reveal deficit in cognitive functions during the early stage in PD. The dopaminergic neurotoxin, MPTP-induced neurodegeneration causes an injury of the basal ganglia and is associated with PD-like behaviors. In this study, we demonstrated that deficits in cognitive functions in MPTP-treated mice were associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and impaired long-term potentiation (LTP) induction in the hippocampal CA1 region. Mice were injected once a day for 5 days with MPTP (25 mg/kg i.p.). The impaired motor coordination was observed 1 or 2 week after MPTP treatment as assessed by rota-rod and beam-walking tasks. In immunoblotting analyses, the levels of tyrosine hydroxylase protein and CaMKII autophosphorylation in the striatum were significantly decreased 1 week after MPTP treatment. By contrast, deficits of cognitive functions were observed 3-4 weeks after MPTP treatment as assessed by novel object recognition and passive avoidance tasks but not Y-maze task. Impaired LTP in the hippocampal CA1 region was also observed in MPTP-treated mice. Concomitant with impaired LTP induction, CaMKII autophosphorylation was significantly decreased 3 weeks after MPTP treatment in the hippocampal CA1 region. Finally, the reduced CaMKII autophosphorylation was closely associated with reduced AMPA-type glutamate receptor subunit 1 (GluR1; Ser-831) phosphorylation in the hippocampal CA1 region of MPTP-treated mice. Taken together, decreased CaMKII activity with concomitant impaired LTP induction in the hippocampus likely account for the learning disability observed in MPTP-treated mice.

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DHA inhibits ER Ca(2+) release and ER stress in astrocytes following in vitro ischemia.

Publication Date: 2012 Feb PMID: 22129278
Authors: Begum, G. - Kintner, D. - Liu, Y. - Cramer, S. W. - Sun, D.
Journal: J Neurochem

J. Neurochem. (2012) 120, 622-630. ABSTRACT: Docosahexaenoic acid (DHA) has neuroprotective effects in several neurodegenerative disease conditions. However, the underlying mechanisms are not well understood. In the present study, we investigated the effects of DHA on astrocyte Ca(2+) signaling under in vitro ischemic conditions (oxygen/glucose deprivation and reoxygenation, OGD/REOX). OGD (2 h) triggered a Ca(2+) (ER) store overload ( approximately 1.9-fold). Ca(2+) uptake by the Ca(2+) (ER) stores was further augmented during REOX and Ca(2+) (ER) was elevated by approximately 4.7-fold at 90 min REOX. Interestingly, Ca(2+) (ER) stores abruptly released Ca(2+) at approximately 120 min REOX and emptied at 160 min REOX. Depletion of Ca(2+) (ER) stores led to delayed elevation of intracellular Ca(2+) concentration (Ca(2+) (cyt) ) and cell death. Activation of the purinergic receptor P2Y1 was responsible for the release of Ca(2+) (ER) . Most importantly, DHA blocked the initial Ca(2+) (ER) store overload, the delayed depletion of Ca(2+) (ER) , and rise in Ca(2+) (cyt) , which was in part via inhibiting d-myo-inositol 1,4,5-triphosphate receptors. The DHA metabolite DiHDoHE exhibited similar effects. DHA also attenuated expression of phosphorylated eukaryotic initiation factor 2alpha and activating transcription factor-4, two ER stress markers, following in vitro ischemia. Taken together, these findings suggest that DHA has protective effects in astrocytes following in vitro ischemia, in part, by inhibiting Ca(2+) dysregulation and ER stress.

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Mutant LGI1 inhibits seizure-induced trafficking of Kv4.2 potassium channels.

Publication Date: 2012 Feb PMID: 22122031
Authors: Smith, S. E. - Xu, L. - Kasten, M. R. - Anderson, M. P.
Journal: J Neurochem

J. Neurochem. (2012) 120, 611-621. ABSTRACT: Activity-dependent redistribution of ion channels mediates neuronal circuit plasticity and homeostasis, and could provide pro-epileptic or compensatory anti-epileptic responses to a seizure. Thalamocortical neurons transmit sensory information to the cerebral cortex and through reciprocal corticothalamic connections are intensely activated during a seizure. Therefore, we assessed whether a seizure alters ion channel surface expression and consequent neurophysiologic function of thalamocortical neurons. We report a seizure triggers a rapid (< 2 h) decrease of excitatory postsynaptic current (EPSC)-like current-induced phasic firing associated with increased transient A-type K(+) current. Seizures also rapidly redistributed the A-type K(+) channel subunit Kv4.2 to the neuronal surface implicating a molecular substrate for the increased K(+) current. Glutamate applied in vitro mimicked the effect, suggesting a direct effect of glutamatergic transmission. Importantly, leucine-rich glioma-inactivated-1 (LGI1), a secreted synaptic protein mutated to cause human partial epilepsy, regulated this seizure-induced circuit response. Human epilepsy-associated dominant-negative-truncated mutant LGI1 inhibited the seizure-induced suppression of phasic firing, increase of A-type K(+) current, and recruitment of Kv4.2 surface expression (in vivo and in vitro). The results identify a response of thalamocortical neurons to seizures involving Kv4.2 surface recruitment associated with dampened phasic firing. The results also identify impaired seizure-induced increases of A-type K(+) current as an additional defect produced by the autosomal dominant lateral temporal lobe epilepsy gene mutant that might contribute to the seizure disorder.

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Hsp70.1 and related lysosomal factors for necrotic neuronal death.

Publication Date: 2012 Feb PMID: 22118687
Authors: Yamashima, T.
Journal: J Neurochem

J. Neurochem. (2012) 120, 477-494. ABSTRACT: Necrosis has long been considered accidental and uncontrolled, but during the last decade, it became clear that necrosis is also a well-orchestrated form of cell demise, being as well programmed as apoptosis. To explain the mechanism of neuronal necrosis after ischemia/reperfusion, the 'calpain-cathepsin hypothesis' formulated in 1998 postulates that the post-ischemic mu-calpain activation compromises integrity of the lysosomal membrane, thereby leading to cathepsin spillage. Another cause of the lysosomal rupture occurring during reperfusion is reactive oxygen species (ROS) that generate 4-hydroxy-2-nonenal (HNE) by oxidation of membrane fatty acids such as linoleic and arachidonic acids. HNE is an endogenous neurotoxin, because HNE-induced carbonylation of the substrate protein shows loss of its function. However, the molecular mechanisms of lysosomal membrane breakdown are still poorly understood; especially, the biochemical cascade how mu-calpain and ROS work together to disrupt lysosomal membrane has remained unclarified. Three independent proteomic analyses of cerebral ischemia, glaucoma, or mild cognitive impairment in primates have altogether suggested that the common substrate of calpain and/or ROS is heat-shock protein 70.1 (Hsp70.1; simply Hsp70, also called Hsp72 or HSPA1), a major protein of the human Hsp70 family. Hsp70.1 serves cytoprotective roles as a guardian of the lysosomal membrane integrity by assisting sphingomyelin degradation or maintaining proper protein folding and recycling as a chaperone. However, calpain-mediated cleavage of Hsp70.1, especially after its carbonylation because of the oxidative stresses, can induce lysosomal rupture. Furthermore, Hsp70.1 dysfunction activates nuclear factor-kappaB (NF-kappaB) signaling that can also promote neurodegeneration. By focusing on Hsp70.1 and related lysosomal factors, this review describes rationale of lysosomal destabilization and rupture for executing programmed neuronal necrosis.

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Astroglial NF-kappaB mediates oxidative stress by regulation of NADPH oxidase in a model of retinal ischemia reperfusion injury.

Publication Date: 2012 Feb PMID: 22118627
Authors: Barakat, D. J. - Dvoriantchikova, G. - Ivanov, D. - Shestopalov, V. I.
Journal: J Neurochem

J. Neurochem. (2012) 120, 586-597. ABSTRACT: Astrocytes undergo rapid activation after injury, which is mediated in part by the transcription factor nuclear factor-kappaB (NF-kappaB). Consequently, activated astrocytes have been shown to induce the NF-kappaB regulated phagocyte NADPH oxidase (PHOX), resulting in elevated production of reactive oxygen species. We investigated the regulatory mechanisms of PHOX-induced oxidative stress in astrocytes and its non-cell-autonomous effects on retinal ganglion cell loss following retinal ischemia-reperfusion (IR) injury. To study PHOX activity and neurotoxicity mediated by glial NF-kappaB, we employed GFAP-IkappaBalpha-dn transgenic mice, where the NF-kappaB canonical pathway is suppressed specifically in astrocytes. Our analysis showed that NF-kappaB activation in astrocytes correlated with an increased expression of PHOX and reactive oxygen species production in primary cells and whole retinas subjected to oxygen-glucose deprivation or IR injury. Selective blockade of NF-kappaB in astrocytes or application of NADPH oxidase inhibitors suppressed retinal ganglion cell loss in co-cultures with astroglia challenged by oxygen-glucose deprivation. Furthermore, genetic suppression of astroglial NF-kappaB reduced oxidative stress in ganglion layer neurons in vivo in retinal IR. Collectively, our results suggest that astroglial NF-kappaB-regulated PHOX activity is a crucial toxicity pathway in the pathogenesis of retinal IR injury.

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Resveratrol mitigates lipopolysaccharide- and Abeta-mediated microglial inflammation by inhibiting the TLR4/NF-kappaB/STAT signaling cascade.

Publication Date: 2012 Feb PMID: 22118570
Authors: Capiralla, H. - Vingtdeux, V. - Zhao, H. - Sankowski, R. - Al-Abed, Y. - Davies, P. - Marambaud, P.
Journal: J Neurochem

J. Neurochem. (2012) 120, 461-472. ABSTRACT: Activation of microglia, the resident macrophages of the brain, around the amyloid plaques is a key hallmark of Alzheimer's disease (AD). Recent evidence in mouse models indicates that microglia are required for the neurodegenerative process of AD. Amyloid-beta (Abeta) peptides, the core components of the amyloid plaques, can trigger microglial activation by interacting with several Toll-like receptors (TLRs), including TLR4. In this study, we show that resveratrol, a natural polyphenol associated with anti-inflammatory effects and currently in clinical trials for AD, prevented the activation of murine RAW 264.7 macrophages and microglial BV-2 cells treated with the TLR4 ligand, lipopolysaccharide (LPS). Resveratrol preferentially inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activation upon LPS stimulation by interfering with IKK and IkappaB phosphorylation, an effect that potently reduced the transcriptional stimulation of several NF-kappaB target genes, including tumor necrosis factor-alpha and interleukin-6. Consequently, downstream phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3 upon LPS stimulation was also inhibited by resveratrol. We found that resveratrol acted upstream in the activation cascade by interfering with TLR4 oligomerization upon receptor stimulation. Resveratrol treatment also prevented the pro-inflammatory effect of fibrillar Abeta on macrophages by potently inhibiting the effect of Abeta on IkappaB phosphorylation, activation of STAT1 and STAT3, and on tumor necrosis factor-alpha and interleukin-6 secretion. Importantly, orally administered resveratrol in a mouse model of cerebral amyloid deposition lowered microglial activation associated with cortical amyloid plaque formation. Together this work provides strong evidence that resveratrol has in vitro and in vivo anti-inflammatory effects against Abeta-triggered microglial activation. Further studies in cell culture systems showed that resveratrol acted via a mechanism involving the TLR4/NF-kappaB/STAT signaling cascade.

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Cholesterol enhances neuron susceptibility to apoptotic stimuli via cAMP/PKA/CREB-dependent up-regulation of Kv2.1.

Publication Date: 2012 Feb PMID: 22118516
Authors: Zhou, M. H. - Yang, G. - Jiao, S. - Hu, C. L. - Mei, Y. A.
Journal: J Neurochem

J. Neurochem. (2012) 120, 502-514. ABSTRACT: Cholesterol is a major component of membrane lipid rafts. It is more abundant in the brain than in other tissues and plays a critical role in maintaining brain function. We report here that a significant enhancement in apoptosis in rat cerebellar granule neurons (CGNs) was observed upon incubation with 5 mM K(+) /serum free (LK-S) medium. Cholesterol enrichment further potentiated CGN apoptosis incubated under LK-S medium. On the contrary, cholesterol depletion using methyl-beta-cyclodextrin protected the CGNs from apoptosis induced by LK-S treatment. Cholesterol enrichment, however, did not induce apoptosis in CGNs that have been incubated with 25 mM K(+) /serum medium. Mechanistically, increased I(K) currents and DNA fragmentation were found in CGNs incubated in LK-S, which was further potentiated in the presence of cholesterol. Cholesterol-treated CGNs also exhibited increased cAMP levels and up-regulation of Kv2.1 expression. Increased levels of activated form of PKA and phospho-CREB further supported activation of the cAMP/PKA pathway upon treatment of CGNs with cholesterol-containing LK-S medium. Conversely, inhibition of PKA or small G protein Gs abolished the increase in I(K) current and the potentiation of Kv2.1 expression, leading to reduced susceptibility of CGNs to LK-S and cholesterol-induced apoptosis. Our results demonstrate that the elevation of membrane cholesterol enhances CGN susceptibility to apoptotic stimuli via cAMP/PKA/CREB-dependent up-regulation of Kv2.1. Our data provide new evidence for the role of cholesterol in eliciting neuronal cell death.

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Activity-dependent survival of developing neocortical neurons depends on PI3K signalling.

Publication Date: 2012 Feb PMID: 22118415
Authors: Wagner-Golbs, A. - Luhmann, H. J.
Journal: J Neurochem

J. Neurochem. (2012) 120, 495-501. ABSTRACT: Spontaneous electrical network activity plays a major role in the control of cell survival in the developing brain. Several intracellular pathways are implicated in transducing electrical activity into gene expression dependent and independent survival signals. These include activation of phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt, activation of Ras and subsequently MAPK/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase and signalling via calcium/calmodulin-dependent protein kinase (CaMK). In the present study, we analyzed the role of these pathways for the control of neuronal survival in different extracellular potassium concentrations ([K(+) ](ex) ). Organotypic neocortical slice cultures prepared from newborn mice were kept in 5.3, 8.0 and 25.0 mM [K(+) ](ex) and treated with specific inhibitors of PI3K, MEK1, CaMKK and a broad spectrum CaMK inhibitor. After 6 h of incubation, slices were immunostained for activated caspase 3 (a-caspase 3) and the number of apoptotic cells was quantified by computer based analysis. We found that in 5.3 and 8.0 mM [K(+) ](ex) only PI3K was important for neuronal survival. When [K(+) ](ex) was raised to 25.0 mM, a concentration above the depolarization block, we found no influence of PI3K on neuronal survival. Our data demonstrate that only the PI3K pathway, and not the MEK1, CaMKK or CaMKs pathway, plays a central role in the regulation of activity-dependent neuronal survival in the developing cerebral cortex.

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Comparison of Cbln1 and Cbln2 functions using transgenic and knockout mice.

Publication Date: 2012 Feb PMID: 22117778
Authors: Rong, Y. - Wei, P. - Parris, J. - Guo, H. - Pattarini, R. - Correia, K. - Li, L. - Kusnoor, S. V. - Deutch, A. Y. - Morgan, J. I.
Journal: J Neurochem

J. Neurochem. (2012) 120, 528-540. ABSTRACT: Cerebellin precursor protein 1 (Cbln1) is the prototype of a family of secreted neuronal glycoproteins (Cbln1-4) and its genetic elimination results in synaptic alterations in cerebellum (CB) and striatum. In CB, Cbln1 acts as a bi-functional ligand bridging pre-synaptic beta-neurexins on granule cells to post-synaptic Grid2 on Purkinje neurons. Although much is known concerning the action of Cbln1, little is known of the function of its other family members. Here, we show that Cbln1 and Cbln2 have similar binding activities to beta-neurexins and Grid2 and the targeted ectopic expression of Cbln2 to Purkinje cells in transgenic mice rescues the cerebellar deficits in Cbln1-null animals: suggesting that the two proteins have redundant function mediated by their common receptor binding properties. Cbln1 and Cbln2 are also co-expressed in the endolysosomal compartment of the thalamic neurons responsible for the synaptic alterations in striatum of Cbln1-null mice. Therefore, to determine whether the two family members have similar functions, we generated Cbln2-null mice. Cbln2-null mice do not show the synaptic alterations evident in striatum of Cbln1-null mice. Thus, Cbln2 can exhibit functional redundancy with Cbln1 in CB but it does not have the same properties as Cbln1 in thalamic neurons, implying one or both utilize different receptors/mechanisms in this brain region.

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Paradoxical roles of serine racemase and d-serine in the G93A mSOD1 mouse model of amyotrophic lateral sclerosis.

Publication Date: 2012 Feb PMID: 22117694
Authors: Thompson, M. - Marecki, J. C. - Marinesco, S. - Labrie, V. - Roder, J. C. - Barger, S. W. - Crow, J. P.
Journal: J Neurochem

J. Neurochem. (2012) 120, 598-610. ABSTRACT: d-Serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of d-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of d-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by d-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades d-serine as well. d-Serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice - the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of d-serine to ALS mice dramatically lowers cord levels of d-serine, leading to changes in the onset and survival very similar to SR deletion. d-Serine treatment also increases cord levels of the alanine-serine-cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases d-serine is not known, these results strongly suggest that SR and d-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.

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Cofilin activation mediates Bax translocation to mitochondria during excitotoxic neuronal death.

Publication Date: 2012 Feb PMID: 22117609
Authors: Posadas, I. - Perez-Martinez, F. C. - Guerra, J. - Sanchez-Verdu, P. - Cena, V.
Journal: J Neurochem

J. Neurochem. (2012) 120, 515-527. ABSTRACT: During excitotoxic neuronal death, Bax translocates to the mitochondria where it plays an important role by contributing to the release of proapoptotic factors. However, how Bax translocates to the mitochondria during excitotoxicity remains poorly understood. Herein, our data suggest the presence of a novel signalling mechanism by which NMDA receptor stimulation promotes Bax translocation. This signalling pathway is triggered by dephosphorylation of cofilin. Once dephosphorylated, cofilin might interact physically with Bax acting as a carrier for it, translocating it to the mitochondria, where it contributes to mitochondrial membrane despolarization, permeabilization and to the release of apoptotic factors, thus leading to neuronal death. Lack-of-function studies indicate that only the Slingshot family of phosphatases, more specifically the enzyme Slingshot 1L phosphatase, but not cronophin participates in the cofilin activation process during excitotoxicity. Indeed, cofilin-mediated Bax translocation seems to be a key event in excitotoxic neuronal death as knock down of either cofilin or Slingshot 1L phosphatase has a marked neuroprotective effect on NMDA-mediated neuronal death. This novel biochemical pathway may therefore be a good target to develop future therapeutic molecules for neurodegenerative diseases.

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Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects.

Publication Date: 2012 Feb PMID: 22103329
Authors: Jafari, S. - Fernandez-Enright, F. - Huang, X. F.
Journal: J Neurochem

J. Neurochem. (2012) 120, 371-384. ABSTRACT: Antipsychotic drugs have various neuropharmacological properties as a result of their structural diversity. Despite their therapeutic benefits, most of the prescribed atypical antipsychotics can induce severe side effects, including weight gain, type II diabetes mellitus, and cardiovascular diseases. Among the developed atypical antipsychotic agents, tetracyclic dibenzodiazepine and thienobenzodiazepine compounds, particularly clozapine and olanzapine, are associated with the greatest weight gain and metabolic disturbances. However, the unique chemical structure of these compounds causes the low risk of side effects reported for typical antipsychotics (e.g. extrapyramidal symptoms and tardive dyskinesia). This report reviews the recent discovery of the potential role of the chemical structure of antipsychotics in their therapeutic properties and metabolic disturbances. By developing structure-activity relationship studies for atypical antipsychotics, we will improve our understanding of the structural modifications of these chemical classes that lead to reduced weight gain, which will be an invaluable step toward the discovery of the next generation of atypical antipsychotics. In this review, we suggest that a novel dibenzodiazepine or thienobenzodiazepine antipsychotic drug with lower affinity for H(1) receptors may significantly advance schizophrenia therapy.

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Cross-functional E3 ligases Parkin and C-terminus Hsp70-interacting protein in neurodegenerative disorders.

Publication Date: 2012 Feb PMID: 22098618
Authors: Kumar, P. - Pradhan, K. - Karunya, R. - Ambasta, R. K. - Querfurth, H. W.
Journal: J Neurochem

J. Neurochem. (2012) 120, 350-370. ABSTRACT: The study of neurodegenerative disorders has had a major impact on our understanding of more fundamental mechanisms underlying neurobiology. Breakthroughs in the genetics of Alzheimer's (AD) and Parkinson's diseases (PD) has resulted in new knowledge in the areas of axonal transport, energy metabolism, protein trafficking/clearance and synaptic physiology. The major neurodegenerative diseases have in common a regional or network pathology associated with abnormal protein accumulation(s) and various degrees of motor or cognitive decline. In AD, beta-amyloids are deposited in extracellular diffuse and compacted plaques as well as intracellularly. There is a major contribution to the disease by the co-existence of an intraneuronal tauopathy. Additionally, PD-like Lewy Bodies (LBs) bearing aggregated alpha-synuclein is present in 40-60% of all AD cases, especially involving amygdala. Amyloid deposits can be degraded or cleared by several mechanisms, including immune-mediated and transcytosis across the blood-brain barrier. Another avenue for disposal involves the lysosome pathway via autophagy. Enzymatic pathways include insulin degradative enzyme and neprilysin. Finally, the co-operative actions of C-terminus Hsp70 interacting protein (CHIP) and Parkin, components of a multiprotein E3 ubiquitin ligase complex, may be a portal to proteasome-mediated degradation. Mutations in the Parkin gene are the most common genetic link to autosomal recessive Parkinson's disease. Parkin catalyzes the post-translational modification of proteins with polyubiquitin, targeting them to the 26S proteasome. Parkin reduces intracellular Abeta(1-42) peptide levels, counteracts its effects on cell death, and reverses its effect to inhibit the proteasome. Additionally, Parkin has intrinsic cytoprotective activity to promote proteasome function and defend against oxidative stress to mitochondria. Parkin and CHIP are also active in amyloid clearance and cytoprotection in vivo. Parkin has cross-functionality in additional neurodegenerative diseases, for instance, to eliminate polyglutamine-expanded proteins, reducing their aggregation and toxicity and reinstate proteasome function. The dual actions of CHIP (molecular co-chaperone and E3 ligase) and Parkin (as E3-ubiquitin ligase and anti-oxidant) may also play a role in suppressing inflammatory reactions in animal models of neurodegeneration. In this review, we focus on the significance of CHIP and Parkin as inducers of amyloid clearance, as cytoprotectants and in the suppression of reactive inflammation. A case is made for more effort to explore whether neurodegeneration associated with proteinopathies can be arrested at early stages by promoting their mutual action.

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Hypoxia inducible factor-1alpha is involved in the neurodegeneration induced by isoflurane in the brain of neonatal rats.

Publication Date: 2012 Feb PMID: 22097881
Authors: Jiang, H. - Huang, Y. - Xu, H. - Sun, Y. - Han, N. - Li, Q. F.
Journal: J Neurochem

J. Neurochem. (2012) 120, 453-460. ABSTRACT: More and more data show isoflurane, a commonly used volatile anesthetic has dual effects on neuron fate. However, the underlying mechanisms that can explain the apparent paradox are poorly understood. Hypoxia inducible factor (HIF)-1alpha, a transcription factor, has been found regulating both prosurvival and prodeath pathways in the CNS. Previously, we found that isoflurane can activate HIF-1alpha under normoxic conditions in vitro and HIF-1alpha has been found to be involved in the pre-conditioning effect of isoflurane in various organs. Here, we investigated whether HIF-1alpha is a contributing factor in the neurodegenration in rodent primary cultured neurons and in developing rat brain. Isoflurane dose-dependently induced apoptotic neurodegeneration in neonatal rats as assessed by S100beta, cleaved caspase 3 and poly-(ADP-ribose) polymerase (PARP), respectively. Notably, isoflurane up-regulates HIF-1alpha protein levels in vivo and in vitro during induction of neurodegeneration. Likewise, isoflurane resulted in a significant elevation of cytosonic calcium levels in neuron cultures. Furthermore, knockdown of HIF-1alpha expression in cultured neurons attenuated isoflurane-induced neurotoxicity. Finally, Morris water maze (MWM) test showed neonatal exposure to isoflurane impaired juvenile learning and memory ability in rats. These findings indicate that HIF-1alpha is involved in the neurodegeneration induced by isoflurane in the brain of neonatal rats, suggesting HIF-1alpha may be a candidate for the dual effects of isoflurane on neuron fate.

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Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease.

Publication Date: 2012 Feb PMID: 22077634
Authors: Sheng, B. - Wang, X. - Su, B. - Lee, H. G. - Casadesus, G. - Perry, G. - Zhu, X.
Journal: J Neurochem

J. Neurochem. (2012) 120, 419-429. ABSTRACT: Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) brain. Our prior studies demonstrated reduced mitochondrial number in susceptible hippocampal neurons in the brain from AD patients and in M17 cells over-expressing familial AD-causing amyloid precursor protein (APP) mutant (APPswe). In the current study, we investigated whether alterations in mitochondrial biogenesis contribute to mitochondrial abnormalities in AD. Mitochondrial biogenesis is regulated by the peroxisome proliferator activator receptor gamma-coactivator 1alpha (PGC-1alpha)-nuclear respiratory factor (NRF)-mitochondrial transcription factor A pathway. Expression levels of PGC-1alpha, NRF 1, NRF 2, and mitochondrial transcription factor A were significantly decreased in both AD hippocampal tissues and APPswe M17 cells, suggesting a reduced mitochondrial biogenesis. Indeed, APPswe M17 cells demonstrated decreased mitochondrial DNA/nuclear DNA ratio, correlated with reduced ATP content, and decreased cytochrome C oxidase activity. Importantly, over-expression of PGC-1alpha could completely rescue while knockdown of PGC-1alpha could exacerbate impaired mitochondrial biogenesis and mitochondrial deficits in APPswe M17 cells, suggesting reduced mitochondrial biogenesis is likely involved in APPswe-induced mitochondrial deficits. We further demonstrated that reduced expression of p-CREB and PGC-1alpha in APPswe M17 cells could be rescued by cAMP in a dose-dependent manner, which could be inhibited by PKA inhibitor H89, suggesting that the PKA/CREB pathway plays a critical role in the regulation of PGC-1alpha expression in APPswe M17 cells. Overall, this study demonstrated that impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD.

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The Discoidin domain receptor 1 gene has a functional A2RE sequence.

Publication Date: 2012 Feb PMID: 22077590
Authors: Roig, B. - Moyano, S. - Martorell, L. - Costas, J. - Vilella, E.
Journal: J Neurochem

J. Neurochem. (2012) 120, 408-418. ABSTRACT: Discoidin domain receptor 1 (DDR1) is expressed in myelin oligodendrocytes and co-localizes with myelin basic protein (MBP). Alternative splicing of DDR1 generates five isoforms designated DDR1a-e. The MBP mRNA contains an hnRNP A2 response element (A2RE) sequence that is recognized by heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, which is responsible for transport of the MBP mRNA to oligodendrocyte processes. We hypothesized that DDR1 could have a functional A2RE sequence. By in silico analysis, we identified an A2RE-like sequence in the human DDR1 mRNA. We observed nuclear and dendrite cytoplasmic immunofluorescence, indicating that DDR1 and hnRNP A2/B1 co-localize in human oligodendrocytes and in differentiated HOG16 cells. The A2RE-like sequence of DDR1 contains the single nucleotide polymorphism rs2267641, and we found that in the human brain, the minor allele is associated with lower and higher levels DDR1b and DDR1c mRNA expression, respectively. Moreover, a positive correlation between DDR1c and the myelin genes myelin-associated glycoprotein and oligodendrocyte lineage transcription factor 2 was found. Differentiated HOG16 cells transfected with an hnRNP A2/B1 siRNA simultaneously show a decrease and an increase in the DDR1c and DDR1b mRNA expression levels, respectively, which was accompanied by a decrease in DDR1 protein levels at the cytoplasmic edges. These results suggest that the DDR1 A2RE sequence is functionally involved in the hnRNP A2/B1-mediated splicing and transport of the DDR1c mRNA.

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alpha-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases.

Publication Date: 2012 Feb PMID: 22060133
Authors: Martin, Z. S. - Neugebauer, V. - Dineley, K. T. - Kayed, R. - Zhang, W. - Reese, L. C. - Taglialatela, G.
Journal: J Neurochem

J. Neurochem. (2012) 120, 440-452. ABSTRACT: Intracellular deposition of fibrillar aggregates of alpha-synuclein (alphaSyn) characterizes neurodegenerative diseases such as Parkinson's disease (PD) and dementia with Lewy bodies. However, recent evidence indicates that small alphaSyn oligomeric aggregates that precede fibril formation may be the most neurotoxic species and can be found extracellularly. This new evidence has changed the view of pathological alphaSyn aggregation from a self-contained cellular phenomenon to an extracellular event and prompted investigation of the putative effects of extracellular alphaSyn oligomers. In this study, we report that extracellular application of alphaSyn oligomers detrimentally impacts neuronal welfare and memory function. We found that oligomeric alphaSyn increased intracellular Ca(2+) levels, induced calcineurin (CaN) activity, decreased cAMP response element-binding protein (CREB) transcriptional activity and resulted in calcineurin-dependent death of human neuroblastoma cells. Similarly, CaN induction and CREB inhibition were observed when alphaSyn oligomers were applied to organotypic brain slices, which opposed hippocampal long-term potentiation. Furthermore, alphaSyn oligomers induced CaN, inhibited CREB and evoked memory impairments in mice that received acute intracerebroventricular injections. Notably, all these events were reversed by pharmacological inhibition of CaN. Moreover, we found decreased active CaN and reduced levels of phosphorylated CREB in autopsy brain tissue from patients affected by dementia with Lewy bodies, which is characterized by deposition of alphaSyn aggregates and progressive cognitive decline. These results indicate that exogenously applied alphaSyn oligomers impact neuronal function and produce memory deficits through mechanisms that involve CaN activation.

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Autophagy: a common road to perdition in acute brain injuries and Alzheimer's disease.

Publication Date: 2012 Feb PMID: 22050458
Authors: Tesco, G.
Journal: J Neurochem

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Clozapine functions through the prefrontal cortex serotonin 1A receptor to heighten neuronal activity via calmodulin kinase II-NMDA receptor interactions.

Publication Date: 2012 Feb PMID: 22044428
Authors: Purkayastha, S. - Ford, J. - Kanjilal, B. - Diallo, S. - Del Rosario Inigo, J. - Neuwirth, L. - El Idrissi, A. - Ahmed, Z. - Wieraszko, A. - Azmitia, E. C. - Banerjee, P.
Journal: J Neurochem

J. Neurochem. (2012) 120, 396-407. ABSTRACT: Aberrant dopamine release in the prefrontal cortex (PFC) is believed to underlie schizophrenia, but the mechanistic pathway through which a widely used antipsychotic, clozapine (Clz), evokes neurotransmitter-releasing electrical stimulation is unclear. We analyzed Clz-evoked regulation of neuronal activity in the PFC by stimulating axons in layers IV and V and recording the electrical effect in the post-synaptic pyramidal cells of layers II and III. We observed a Clz-evoked increase in population spike (PS), which was mediated by serotonin 1A receptor (5-HT(1A) -R), phospholipase Cbeta, and Ca(2+) /calmodulin-dependent protein kinase II (CaMKII). Immunoblotting demonstrated that the Clz-activation of CaMKII was 5-HT(1A) -R-mediated. Intriguingly, the NMDA receptor (NMDA-R) antagonist (+/-)2-amino-5-phosphonovaleric acid (APV) eliminated the Clz-mediated increase in PS, suggesting that the 5-HT(1A) -R, NMDA-R and CaMKII form a synergistic triad, which boosts excitatory post-synaptic potential (EPSP), thereby enhancing PS. In corroboration, Clz as well as NMDA augmented field EPSP (fEPSP), and WAY100635 (a 5-HT(1A) -R antagonist), APV, and a CaMKII inhibitor eliminated this increase. As previously shown, CaMKII binds to the NMDA-R 2B (NR2B) subunit to become constitutively active, thereby inducing alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor recruitment to the post-synaptic membrane and an increase in fEPSP. Co-immunoprecipitation demonstrated that Clz potentiates interactions among CaMKII, NR2B, and 5-HT(1A) -R, possibly in the membrane rafts of the post-synaptic density (PSD), because pretreatment with methyl-beta-cyclodextrin (MCD), an agent that disrupts rafts, inhibited both co-immunoprecipitation as well as fEPSP. In summary, Clz functions in the PFC by orchestrating a synergism among 5-HT(1A) -R, CaMKII, and NMDA-R, which augments excitability in the PFC neurons of layers II/III.

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beta-Apptists and Tauists, it is time for a sermon from the book of biogenesis.

Publication Date: 2012 Feb PMID: 22035261
Authors: Swerdlow, R. H.
Journal: J Neurochem

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Why are hippocampal CA1 neurons vulnerable but motor cortex neurons resistant to transient ischemia?

Publication Date: 2012 Feb PMID: 22017466
Authors: Zhu, H. - Yoshimoto, T. - Imajo-Ohmi, S. - Dazortsava, M. - Mathivanan, A. - Yamashima, T.
Journal: J Neurochem

J. Neurochem. (2012) 120, 574-585. ABSTRACT: It is well-known that heat-shock protein 70.1 (Hsp70.1), a major protein of the human Hsp70 family, plays cytoprotective roles by both its chaperone function and stabilization of lysosomal membranes. Recently, we found that calpain-mediated cleavage of carbonylated Hsp70.1 in the hippocampal cornu Ammonis1 (CA1) contributes to neuronal death after transient global ischemia. This study aims to elucidate the differential neuronal vulnerability between the motor cortex and CA1 sector against ischemia/reperfusion. Fluoro-Jade B staining and terminal deoxynucleotidyl transferase-mediated dUTP-nick-end-labeling analysis of the monkey brain undergoing 20 min whole brain ischemia followed by reperfusion, showed that the motor cortex is significantly resistant to the ischemic insult compared with CA1. Up-regulation of Hsp70.1 but absence of its cleavage by calpain facilitated its binding with NF-kappaB p65/IkappaBalpha complex to minimize NF-kappaB p65 activation, which contributed to a neuroprotection in the motor cortex. In contrast, because activated mu-calpain cleaved carbonylated Hsp70.1 in CA1, the resultant Hsp70.1 dysfunction not only destabilized lysosomal membrane but also induced a sustained activation of NF-kappaB p65, both of which resulted in delayed neuronal death. We propose that the cascades underlying lysosomal stabilization and regulating NF-kappaB activation by Hsp70.1 may influence neuronal survival/death after the ischemia/reperfusion.

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Aberrant striatal dopamine transmitter dynamics in brain-derived neurotrophic factor-deficient mice.

Publication Date: 2012 Feb PMID: 21988371
Authors: Bosse, K. E. - Maina, F. K. - Birbeck, J. A. - France, M. M. - Roberts, J. J. - Colombo, M. L. - Mathews, T. A.
Journal: J Neurochem

J. Neurochem. (2012) 120, 385-395. ABSTRACT: Brain-derived neurotrophic factor (BDNF) modulates the synaptic transmission of several monoaminergic neuronal systems, including forebrain dopamine-containing neurons. Recent evidence shows a strong correlation between neuropsychiatric disorders and BDNF hypofunction. The aim of the present study was to characterize the effect of low endogenous levels of BDNF on dopamine system function in the caudate-putamen using heterozygous BDNF (BDNF(+/-) ) mice. Apparent extracellular dopamine levels in the caudate-putamen, determined by quantitative microdialysis, were significantly elevated in BDNF(+/-) mice compared with wildtype controls (12 vs. 5 nM, respectively). BDNF(+/-) mice also had a potentiated increase in dopamine levels following potassium (120 mM)-stimulation (10-fold) relative to wildtype controls (6-fold). Slice fast-scan cyclic voltammetry revealed that BDNF(+/-) mice had reductions in both electrically evoked dopamine release and dopamine uptake rates in the caudate-putamen. Superfusion of BDNF led to partial recovery of the electrically stimulated dopamine release response in BDNF(+/-) mice. Conversely, tissue accumulation of L-3,4-dihydroxyphenylalanine, extracellular levels of dopamine metabolites, and spontaneous locomotor activity were unaltered. Together, this study indicates that endogenous BDNF influences dopamine system homeostasis by regulating the release and uptake dynamics of pre-synaptic dopamine transmission.

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Autophagosomes accumulation is associated with beta-amyloid deposits and secondary damage in the thalamus after focal cortical infarction in hypertensive rats.

Publication Date: 2012 Feb PMID: 21950964
Authors: Zhang, J. - Zhang, Y. - Li, J. - Xing, S. - Li, C. - Li, Y. - Dang, C. - Fan, Y. - Yu, J. - Pei, Z. - Zeng, J.
Journal: J Neurochem

J. Neurochem. (2012) 120, 564-573. ABSTRACT: Focal cerebral cortical infarction after distal middle cerebral artery occlusion causes beta-amyloid deposition and secondary neuronal degeneration in the ipsilateral ventroposterior nucleus of the thalamus. Several studies suggest that autophagy is an active pathway for beta-amyloid peptide generation. This study aimed to investigate the role of autophagy in thalamic beta-amyloid deposition and neuronal degeneration after cerebral cortical infarction in hypertensive rats. At 7 and 14 days after middle cerebral artery occlusion, neuronal death and beta-amyloid deposits were evident in the ipsilateral ventroposterior nucleus, and the activity of beta-site amyloid precursor protein (APP)-cleaving enzyme 1, required for beta-amyloid peptide generation, was elevated in the thalamus. In correlation, both the number of cells showing punctate microtubule-associated protein 1A light chain 3 fluorescence and levels of light chain 3-II protein, an autophagosome marker, were markedly increased. Notably, most of the cells that over-expressed beta-site APP-cleaving enzyme 1 displayed punctate light chain 3 staining. Furthermore, the inhibition of autophagy with 3-methyladenine significantly reduced the thalamic neuronal damage, beta-amyloid deposits, and beta-site APP-cleaving enzyme 1 activity. These results suggest that autophagosomes accumulate within thalamic cells after cerebral cortical infarction, which is associated with thalamic beta-amyloid deposition and secondary neuronal degeneration via elevation of beta-site APP-cleaving enzyme 1 level.

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Pin1 inhibition activates cyclin D and produces neurodegenerative pathology.

Publication Date: 2012 Feb PMID: 21443524
Authors: Atabay, K. D. - Karabay, A.
Journal: J Neurochem

J. Neurochem. (2012) 120, 430-439. ABSTRACT: Abnormal cell cycle events are increasingly becoming important attributes of neurodegenerative pathology. Pin1 is a crucial target of neurodegeneration in relation to its functions regarding these abnormal cell cycle events in neurons. Pin1 is majorly involved in many aspects of cell cycle regulation and it has also been suggested to have a neuroprotective function against neurodegenerative pathologies. Oxidative dysregulation of Pin1 affects not only normal tau regulation, eventually causing tangle formation, but also cell cycle regulation in neurons. Presence of cell cycle proteins has been shown in many neurodegenerative diseases. Importantly, many of these proteins have physical interactions with Pin1. Hence, understanding Pin1's role in abnormal cell cycle re-entry is critical in terms of finding new approaches for the future therapeutic options treating neurodegenerative pathologies. Here, we show that inhibition of Pin1 by its selective inhibitor juglone leads to up-regulation of cyclinD1, phospho-tau, and caspase 3, producing apoptosis in cultured rat hippocampal neurons. We also observed axonal retraction with a change in sub-cellular localizations of cyclins. Therefore, Pin1 dysregulation, in relation to its role in cell cycle regulation in neurons, may have profound effects in the progression of neurodegenerative pathology, making it a possible crucial target behind many neurodegenerative diseases.

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