Nature Neuroscience

Channel properties reveal differential expression of TARPed and TARPless AMPARs in stargazer neurons.

Publication Date: 2012 May 13 PMID: 22581185
Authors: Bats, C. - Soto, D. - Studniarczyk, D. - Farrant, M. - Cull-Candy, S. G.
Journal: Nat Neurosci

Dynamic regulation of calcium-permeable AMPA receptors (CP-AMPARs) is important for normal synaptic transmission, plasticity and pathological changes. Although the involvement of transmembrane AMPAR regulatory proteins (TARPs) in trafficking of calcium-impermeable AMPARs (CI-AMPARs) has been extensively studied, their role in the surface expression and function of CP-AMPARs remains unclear. We examined AMPAR-mediated currents in cerebellar stellate cells from stargazer mice, which lack the prototypical TARP stargazin (gamma-2). We found a marked increase in the contribution of CP-AMPARs to synaptic responses, indicating that, unlike CI-AMPARs, these can localize at synapses in the absence of gamma-2. In contrast with CP-AMPARs in extrasynaptic regions, synaptic CP-AMPARs displayed an unexpectedly low channel conductance and strong block by intracellular spermine, suggesting that they were 'TARPless'. As a proof of principle that TARP association is not an absolute requirement for AMPAR clustering at synapses, miniature excitatory postsynaptic currents mediated by TARPless AMPARs were readily detected in stargazer granule cells following knockdown of their only other TARP, gamma-7.

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Nonlinear analysis of macaque V1 color tuning reveals cardinal directions for cortical color processing.

Publication Date: 2012 May 13 PMID: 22581184
Authors: Horwitz, G. D. - Hass, C. A.
Journal: Nat Neurosci

Understanding color vision requires knowing how signals from the three classes of cone photoreceptor are combined in the cortex. We recorded from individual neurons in the primary visual cortex (V1) of awake monkeys while an automated, closed-loop system identified stimuli that differed in cone contrast but evoked the same response. We found that isoresponse surfaces for half the neurons were planar, which is consistent with linear processing. The remaining isoresponse surfaces were nonplanar. Some were cup-shaped, indicating sensitivity to only a narrow region of color space. Others were ellipsoidal, indicating sensitivity to all color directions. The major and minor axes of these nonplanar surfaces were often aligned to a set of three color directions that were previously identified in perceptual experiments. These results suggest that many V1 neurons combine cone signals nonlinearly and provide a new framework in which to decipher color processing in V1.

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Activation of adult-born neurons facilitates learning and memory.

Publication Date: 2012 May 13 PMID: 22581183
Authors: Alonso, M. - Lepousez, G. - Wagner, S. - Bardy, C. - Gabellec, M. M. - Torquet, N. - Lledo, P. M.
Journal: Nat Neurosci

Thousand of local interneurons reach the olfactory bulb of adult rodents every day, but the functional effect of this process remains elusive. By selectively expressing channelrhodopsin in postnatal-born mouse neurons, we found that their activation accelerated difficult odor discrimination learning and improved memory. This amelioration was seen when photoactivation occurred simultaneously with odor presentation, but not when odor delivery lagged by 500 ms. In addition, learning was facilitated when light flashes were delivered at 40 Hz, but not at 10 Hz. Both in vitro and in vivo electrophysiological recordings of mitral cells revealed that 40-Hz stimuli produced enhanced GABAergic inhibition compared with 10-Hz stimulation. Facilitation of learning occurred specifically when photoactivated neurons were generated during adulthood. Taken together, our results demonstrate an immediate causal relationship between the activity of adult-born neurons and the function of the olfactory bulb circuit.

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Gating and control of primary visual cortex by pulvinar.

Publication Date: 2012 May 6 PMID: 22561455
Authors: Purushothaman, G. - Marion, R. - Li, K. - Casagrande, V. A.
Journal: Nat Neurosci

The primary visual cortex (V1) receives its driving input from the eyes via the lateral geniculate nucleus (LGN) of the thalamus. The lateral pulvinar nucleus of the thalamus also projects to V1, but this input is not well understood. We manipulated lateral pulvinar neural activity in prosimian primates and assessed the effect on supra-granular layers of V1 that project to higher visual cortex. Reversibly inactivating lateral pulvinar prevented supra-granular V1 neurons from responding to visual stimulation. Reversible, focal excitation of lateral pulvinar receptive fields increased the visual responses in coincident V1 receptive fields fourfold and shifted partially overlapping V1 receptive fields toward the center of excitation. V1 responses to regions surrounding the excited lateral pulvinar receptive fields were suppressed. LGN responses were unaffected by these lateral pulvinar manipulations. Excitation of lateral pulvinar after LGN lesion activated supra-granular layer V1 neurons. Thus, lateral pulvinar is able to powerfully control and gate information outflow from V1.

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Large-scale cortical correlation structure of spontaneous oscillatory activity.

Publication Date: 2012 May 6 PMID: 22561454
Authors: Hipp, J. F. - Hawellek, D. J. - Corbetta, M. - Siegel, M. - Engel, A. K.
Journal: Nat Neurosci

Little is known about the brain-wide correlation of electrophysiological signals. We found that spontaneous oscillatory neuronal activity exhibited frequency-specific spatial correlation structure in the human brain. We developed an analysis approach that discounts spurious correlation of signal power caused by the limited spatial resolution of electrophysiological measures. We applied this approach to source estimates of spontaneous neuronal activity reconstructed from magnetoencephalography. Overall, correlation of power across cortical regions was strongest in the alpha to beta frequency range (8-32 Hz) and correlation patterns depended on the underlying oscillation frequency. Global hubs resided in the medial temporal lobe in the theta frequency range (4-6 Hz), in lateral parietal areas in the alpha to beta frequency range (8-23 Hz) and in sensorimotor areas for higher frequencies (32-45 Hz). Our data suggest that interactions in various large-scale cortical networks may be reflected in frequency-specific power envelope correlations.

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Contribution of visual and circadian neural circuits to memory for prolonged mating induced by rivals.

Publication Date: 2012 May 6 PMID: 22561453
Authors: Kim, W. J. - Jan, L. Y. - Jan, Y. N.
Journal: Nat Neurosci

Rival exposure causes Drosophila melanogaster males to prolong mating. Longer mating duration (LMD) may enhance reproductive success, but its underlying mechanism is currently unknown. We found that LMD is context dependent and can be induced solely via visual stimuli. In addition, we found that LMD involves neural circuits that are important for visual memory, including central neurons in the ellipsoid body, but not the mushroom bodies or the fan-shaped bodies, and may rely on the rival exposure memory lasting for several hours. LMD is affected by a subset of learning and memory mutants. LMD depends on the circadian clock genes timeless and period, but not Clock or cycle, and persists in many arrhythmic conditions. Moreover, LMD critically depends on a subset of pigment dispersing factor neurons rather than the entire circadian neural circuit. Our study thus delineates parts of the molecular and cellular basis for LMD, a plastic social behavior elicited by visual cues.

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Preso1 dynamically regulates group I metabotropic glutamate receptors.

Publication Date: 2012 May 6 PMID: 22561452
Authors: Hu, J. H. - Yang, L. - Kammermeier, P. J. - Moore, C. G. - Brakeman, P. R. - Tu, J. - Yu, S. - Petralia, R. S. - Li, Z. - Zhang, P. W. - Park, J. M. - Dong, X. - Xiao, B. - Worley, P. F.
Journal: Nat Neurosci

Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are G protein-coupled receptors (GPCRs) that are expressed at excitatory synapses in brain and spinal cord. GPCRs are often negatively regulated by specific G protein-coupled receptor kinases and subsequent binding of arrestin-like molecules. Here we demonstrate an alternative mechanism in which group I mGluRs are negatively regulated by proline-directed kinases that phosphorylate the binding site for the adaptor protein Homer, and thereby enhance mGluR-Homer binding to reduce signaling. This mechanism is dependent on a multidomain scaffolding protein, Preso1, that binds mGluR, Homer and proline-directed kinases and that is required for their phosphorylation of mGluR at the Homer binding site. Genetic ablation of Preso1 prevents dynamic phosphorylation of mGluR5, and Preso1(-/-) mice exhibit sustained, mGluR5-dependent inflammatory pain that is linked to enhanced mGluR signaling. Preso1 creates a microdomain for proline-directed kinases with broad substrate specificity to phosphorylate mGluR and to mediate negative regulation.

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Visual neurotransmission in Drosophila requires expression of Fic in glial capitate projections.

Publication Date: 2012 Apr 29 PMID: 22544313
Authors: Rahman, M. - Ham, H. - Liu, X. - Sugiura, Y. - Orth, K. - Kramer, H.
Journal: Nat Neurosci

Fic domains can catalyze the addition of adenosine monophosphate to target proteins. To date, the function of Fic domain proteins in eukaryotic physiology remains unknown. We generated genetic models of the single Drosophila Fic domain-containing protein, Fic. Flies lacking Fic were viable and fertile, but blind. Photoreceptor cells depolarized normally following light stimulation, but failed to activate postsynaptic neurons, as indicated by the loss of ON transients in electroretinograms, consistent with a neurotransmission defect. Functional rescue of neurotransmission required expression of enzymatically active Fic on capitate projections of glia cells, but not neurons, supporting a role in the recycling of the visual neurotransmitter histamine. Histamine levels were reduced in the lamina of Fic null flies, and dietary histamine partially restored ON transients. These findings establish a previously unknown regulatory mechanism in visual neurotransmission and provide, to the best of our knowledge, the first evidence for a role of glial capitate projections in neurotransmitter recycling.

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Calbindin controls release probability in ventral tegmental area dopamine neurons.

Publication Date: 2012 Apr 29 PMID: 22544312
Authors: Pan, P. Y. - Ryan, T. A.
Journal: Nat Neurosci

Relatively little is known about the molecular control of midbrain dopamine release. Using high-fidelity imaging of pHluorin-tagged vesicular monoamine transporter 2 in dopamine neurons, we found that exocytosis was more loosely coupled to calcium entry than in fast synapses. In ventral tegmental area neurons, this allows exocytosis to be efficiently controlled by a native fast calcium buffer, calbindin-D28k, maintaining a lower vesicular release probability compared with substantia nigra neurons.

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Adolescent impulsivity phenotypes characterized by distinct brain networks.

Publication Date: 2012 Apr 29 PMID: 22544311
Authors: Whelan, R. - Conrod, P. J. - Poline, J. B. - Lourdusamy, A. - Banaschewski, T. - Barker, G. J. - Bellgrove, M. A. - Buchel, C. - Byrne, M. - Cummins, T. D. - Fauth-Buhler, M. - Flor, H. - Gallinat, J. - Heinz, A. - Ittermann, B. - Mann, K. - Martinot, J. L. - Lalor, E. C. - Lathrop, M. - Loth, E. - Nees, F. - Paus, T. - Rietschel, M. - Smolka, M. N. - Spanagel, R. - Stephens, D. N. - Struve, M. - Thyreau, B. - Vollstaedt-Klein, S. - Robbins, T. W. - Schumann, G. - Garavan, H.
Journal: Nat Neurosci

The impulsive behavior that is often characteristic of adolescence may reflect underlying neurodevelopmental processes. Moreover, impulsivity is a multi-dimensional construct, and it is plausible that distinct brain networks contribute to its different cognitive, clinical and behavioral aspects. As these networks have not yet been described, we identified distinct cortical and subcortical networks underlying successful inhibitions and inhibition failures in a large sample (n = 1,896) of 14-year-old adolescents. Different networks were associated with drug use (n = 1,593) and attention-deficit hyperactivity disorder symptoms (n = 342). Hypofunctioning of a specific orbitofrontal cortical network was associated with likelihood of initiating drug use in early adolescence. Right inferior frontal activity was related to the speed of the inhibition process (n = 826) and use of illegal substances and associated with genetic variation in a norepinephrine transporter gene (n = 819). Our results indicate that both neural endophenotypes and genetic variation give rise to the various manifestations of impulsive behavior.

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Distinct roles for direct and indirect pathway striatal neurons in reinforcement.

Publication Date: 2012 Apr 29 PMID: 22544310
Authors: Kravitz, A. V. - Tye, L. D. - Kreitzer, A. C.
Journal: Nat Neurosci

Dopamine signaling is implicated in reinforcement learning, but the neural substrates targeted by dopamine are poorly understood. We bypassed dopamine signaling itself and tested how optogenetic activation of dopamine D1 or D2 receptor-expressing striatal projection neurons influenced reinforcement learning in mice. Stimulating D1 receptor-expressing neurons induced persistent reinforcement, whereas stimulating D2 receptor-expressing neurons induced transient punishment, indicating that activation of these circuits is sufficient to modify the probability of performing future actions.

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On the scent of mitochondrial calcium.

Publication Date: 2012 PMID: 22534577
Authors: Zufall, F.
Journal: Nat Neurosci

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Fat incites tanycytes to neurogenesis.

Publication Date: 2012 PMID: 22534576
Authors: Dietrich, M. O. - Horvath, T. L.
Journal: Nat Neurosci

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Astrocytes join the plasticity party.

Publication Date: 2012 PMID: 22534575
Authors: Rossi, D. J.
Journal: Nat Neurosci

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Is the reward really worth it?

Publication Date: 2012 PMID: 22534574
Authors: Kennerley, S. W.
Journal: Nat Neurosci

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Focus on social neuroscience.

Publication Date: 2012 PMID: 22534573
Authors:
Journal: Nat Neurosci

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SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity.

Publication Date: 2012 Apr 22 PMID: 22522402
Authors: Chamberlain, S. E. - Gonzalez-Gonzalez, I. M. - Wilkinson, K. A. - Konopacki, F. A. - Kantamneni, S. - Henley, J. M. - Mellor, J. R.
Journal: Nat Neurosci

Phosphorylation or SUMOylation of the kainate receptor (KAR) subunit GluK2 have both individually been shown to regulate KAR surface expression. However, it is unknown whether phosphorylation and SUMOylation of GluK2 are important for activity-dependent KAR synaptic plasticity. We found that protein kinase C-mediated phosphorylation of GluK2 at serine 868 promotes GluK2 SUMOylation at lysine 886 and that both of these events are necessary for the internalization of GluK2-containing KARs that occurs during long-term depression of KAR-mediated synaptic transmission at rat hippocampal mossy fiber synapses. Conversely, phosphorylation of GluK2 at serine 868 in the absence of SUMOylation led to an increase in KAR surface expression by facilitating receptor recycling between endosomal compartments and the plasma membrane. Our results suggest a role for the dynamic control of synaptic SUMOylation in the regulation of KAR synaptic transmission and plasticity.

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Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors.

Publication Date: 2012 Apr 22 PMID: 22522401
Authors: Lee, Y. - Katyal, S. - Downing, S. M. - Zhao, J. - Russell, H. R. - McKinnon, P. J.
Journal: Nat Neurosci

The rapid proliferation of progenitors during neurogenesis requires a stringent genomic maintenance program to ensure transmission of genetic fidelity. However the essential factors that govern neural progenitor genome integrity are unknown. Here we report that conditional inactivation of mouse TopBP1, a protein linked to DNA replication, and a key activator of the DNA damage response kinase ATR (ataxia telangiectasia and rad3-related) is critical for maintenance of early-born neural progenitors. During cortical development TopBP1 prevented replication-associated DNA damage in Emx1-progenitors which otherwise resulted in profound tissue ablation. Notably, disrupted neurogenesis in TopBP1-depleted tissues was substantially rescued by inactivation of p53 but not of ATM. Our data establish that TopBP1 is essential for preventing replication-associated DNA strand breaks, but is not essential per se for DNA replication. Thus, TopBP1 is crucial for maintaining genome integrity in the early progenitors that drive neurogenesis.

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Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons.

Publication Date: 2012 Apr 22 PMID: 22522400
Authors: Dietz, D. M. - Sun, H. - Lobo, M. K. - Cahill, M. E. - Chadwick, B. - Gao, V. - Koo, J. W. - Mazei-Robison, M. S. - Dias, C. - Maze, I. - Damez-Werno, D. - Dietz, K. C. - Scobie, K. N. - Ferguson, D. - Christoffel, D. - Ohnishi, Y. - Hodes, G. E. - Zheng, Y. - Neve, R. L. - Hahn, K. M. - Russo, S. J. - Nestler, E. J.
Journal: Nat Neurosci

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure.

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