Neuropsychiatry Journals

Journal of the International Neuropsychological Society, Volume 16 Supplement S2 JINS publishes peer-reviewed articles covering all areas of neuropsychology with either an experimental or clinical focus. Original research with an option for fast, short communications, critical reviews and dialogues that make a theoretical contribution to the field, and transactions of the annual meetings of the International Neuropsychological Society are published. Contributions reflect the interest of all areas of neuropsychology, including but not limited to: development of cognitive processes, brain-behavior relationships, adult and child neuropsychology, disorders of speech and language, and very importantly the interface of neuropsychology with related areas, such as cognitive neuroscience, behavioral neurology and neuropsychiatry.

Publication Date: 2010 Aug 29 PMID: 20802490
Authors: Evers, D. M. - Matta, J. A. - Hoe, H. S. - Zarkowsky, D. - Lee, S. H. - Isaac, J. T. - Pak, D. T.
Journal: Nat Neurosci

Trafficking of AMPA receptors (AMPARs) is important for many forms of synaptic plasticity. However, the link between activity and resulting synaptic alterations is not fully understood. We identified a direct interaction between N-ethylmaleimide-sensitive fusion protein (NSF), an ATPase involved in membrane fusion events and stabilization of surface AMPARs, and Polo-like kinase- 2 (Plk2), an activity-inducible kinase that homeostatically decreases excitatory synapse number and strength. Plk2 disrupted the interaction of NSF with the GluA2 subunit of AMPARs, promoting extensive loss of surface GluA2 in rat hippocampal neurons, greater association of GluA2 with adaptor proteins PICK1 and GRIP1, and decreased synaptic AMPAR current. Plk2 engagement of NSF, but not Plk2 kinase activity, was required for this mechanism and occurred through a motif in the Plk2 protein that was independent of the canonical polo box interaction sites. These data reveal that heightened synaptic activity, acting through Plk2, leads to homeostatic decreases in surface AMPAR expression via the direct dissociation of NSF from GluA2.

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Publication Date: 2010 Aug 29 PMID: 20802489
Authors: Padmanabhan, K. - Urban, N. N.
Journal: Nat Neurosci

Although examples of variation and diversity exist throughout the nervous system, their importance remains a source of debate. Even neurons of the same molecular type have notable intrinsic differences. Largely unknown, however, is the degree to which these differences impair or assist neural coding. We examined the outputs from a single type of neuron, the mitral cells of the mouse olfactory bulb, to identical stimuli and found that each cell's spiking response was dictated by its unique biophysical fingerprint. Using this intrinsic heterogeneity, diverse populations were able to code for twofold more information than their homogeneous counterparts. In addition, biophysical variability alone reduced pair-wise output spike correlations to low levels. Our results indicate that intrinsic neuronal diversity is important for neural coding and is not simply the result of biological imprecision.

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Publication Date: 2010 Sep PMID: 20740034
Authors: Dave, K. A.
Journal: Nat Neurosci



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Publication Date: 2010 Sep PMID: 20740033
Authors: Sirotin, Y. B. - Das, A.
Journal: Nat Neurosci



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Publication Date: 2010 Sep PMID: 20740032
Authors: Smart, T. G.
Journal: Nat Neurosci



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Publication Date: 2010 Sep PMID: 20740031
Authors: Hopf, F. W. - Bonci, A.
Journal: Nat Neurosci



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Publication Date: 2010 Sep PMID: 20740030
Authors: Feng, J. - Nestler, E. J.
Journal: Nat Neurosci



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Publication Date: 2010 Sep PMID: 20740029
Authors: Roskies, A.
Journal: Nat Neurosci



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Publication Date: 2010 Sep PMID: 20740028
Authors:
Journal: Nat Neurosci



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Publication Date: 2010 Sep PMID: 20729846
Authors: Schlosburg, J. E. - Blankman, J. L. - Long, J. Z. - Nomura, D. K. - Pan, B. - Kinsey, S. G. - Nguyen, P. T. - Ramesh, D. - Booker, L. - Burston, J. J. - Thomas, E. A. - Selley, D. E. - Sim-Selley, L. J. - Liu, Q. S. - Lichtman, A. H. - Cravatt, B. F.
Journal: Nat Neurosci

Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB(1)) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB(1) receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB(1) receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.

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Publication Date: 2010 Sep PMID: 20729845
Authors: Onishi, A. - Peng, G. H. - Chen, S. - Blackshaw, S.
Journal: Nat Neurosci

Selective expression of retinal cone opsin genes is essential for color vision, but the mechanism mediating this process is poorly understood. Both vertebrate rod and medium wavelength-sensitive (M) cone photoreceptors differentiate by repression of a short wavelength-sensitive (S) cone differentiation program. We found that Pias3 acts in mouse cone photoreceptors to activate expression of M opsin and repress expression of S opsin, with the transcription factors Trbeta2 and Rxrgamma mediating preferential expression of Pias3 in M cones. Finally, we observed that Pias3 directly regulated M and S cone opsin expression by modulating the cone-enriched transcription factors Rxrgamma, Roralpha and Trbeta1. Our results indicate that Pias3-dependent SUMOylation of photoreceptor-specific transcription factors is a common mechanism that controls both rod and cone photoreceptor subtype specification, regulating distinct molecular targets in the two cell types.

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Publication Date: 2010 Sep PMID: 20729844
Authors: Laplant, Q. - Vialou, V. - Covington, H. E. 3rd - Dumitriu, D. - Feng, J. - Warren, B. L. - Maze, I. - Dietz, D. M. - Watts, E. L. - Iniguez, S. D. - Koo, J. W. - Mouzon, E. - Renthal, W. - Hollis, F. - Wang, H. - Noonan, M. A. - Ren, Y. - Eisch, A. J. - Bolanos, C. A. - Kabbaj, M. - Xiao, G. - Neve, R. L. - Hurd, Y. L. - Oosting, R. S. - Fan, G. - Morrison, J. H. - Nestler, E. J.
Journal: Nat Neurosci

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.

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Publication Date: 2010 Sep PMID: 20729843
Authors: Chang, M. C. - Park, J. M. - Pelkey, K. A. - Grabenstatter, H. L. - Xu, D. - Linden, D. J. - Sutula, T. P. - McBain, C. J. - Worley, P. F.
Journal: Nat Neurosci

Homeostatic synaptic scaling alters the strength of synapses to compensate for prolonged changes in network activity and involves both excitatory and inhibitory neurons. The immediate-early gene Narp (neuronal activity-regulated pentraxin) encodes a secreted synaptic protein that can bind to and induce clustering of AMPA receptors (AMPARs). We found that Narp prominently accumulated at excitatory synapses on parvalbumin-expressing interneurons (PV-INs). Increasing network activity resulted in a homeostatic increase of excitatory synaptic strength onto PV-INs that increased inhibitory drive and this response was absent in neurons cultured from Narp(-/-) mice. Activity-dependent changes in the strength of excitatory inputs on PV-INs in acute hippocampal slices were also dependent on Narp and Narp(-/-) mice had increased sensitivity to kindling-induced seizures. We propose that Narp recruits AMPARs at excitatory synapses onto PV-INs to rebalance network excitation/inhibition dynamics following episodes of increased circuit activity.

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Publication Date: 2010 Sep PMID: 20711186
Authors: Deng, J. V. - Rodriguiz, R. M. - Hutchinson, A. N. - Kim, I. H. - Wetsel, W. C. - West, A. E.
Journal: Nat Neurosci

MeCP2 is a methyl DNA-binding transcriptional regulator that contributes to the development and function of CNS synapses; however, the requirement for MeCP2 in stimulus-regulated behavioral plasticity is not fully understood. Here we show that acute viral manipulation of MeCP2 expression in the nucleus accumbens (NAc) bidirectionally modulates amphetamine (AMPH)-induced conditioned place preference. Mecp2 hypomorphic mutant mice have more NAc GABAergic synapses and show deficient AMPH-induced structural plasticity of NAc dendritic spines. Furthermore, these mice show deficient plasticity of striatal immediate early gene inducibility after repeated AMPH administration. Notably, psychostimulants induce phosphorylation of MeCP2 at Ser421, a site that regulates MeCP2's function as a repressor. Phosphorylation is selectively induced in GABAergic interneurons of the NAc, and its extent strongly predicts the degree of behavioral sensitization. These data reveal new roles for MeCP2 both in mesolimbocortical circuit development and in the regulation of psychostimulant-induced behaviors.

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Publication Date: 2010 Sep PMID: 20711185
Authors: Im, H. I. - Hollander, J. A. - Bali, P. - Kenny, P. J.
Journal: Nat Neurosci

The X-linked transcriptional repressor methyl CpG binding protein 2 (MeCP2), known for its role in the neurodevelopmental disorder Rett syndrome, is emerging as an important regulator of neuroplasticity in postmitotic neurons. Cocaine addiction is commonly viewed as a disorder of neuroplasticity, but the potential involvement of MeCP2 has not been explored. Here we identify a key role for MeCP2 in the dorsal striatum in the escalating cocaine intake seen in rats with extended access to the drug, a process that mimics the increasingly uncontrolled cocaine use seen in addicted humans. MeCP2 regulates cocaine intake through homeostatic interactions with microRNA-212 (miR-212) to control the effects of cocaine on striatal brain-derived neurotrophic factor (BDNF) levels. These data suggest that homeostatic interactions between MeCP2 and miR-212 in dorsal striatum may be important in regulating vulnerability to cocaine addiction.

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Publication Date: 2010 Sep PMID: 20711184
Authors: Altimus, C. M. - Guler, A. D. - Alam, N. M. - Arman, A. C. - Prusky, G. T. - Sampath, A. P. - Hattar, S.
Journal: Nat Neurosci

In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. Using mice that lack functional rods or in which rods are the only functional photoreceptors, we found that rods were solely responsible for photoentrainment at scotopic light intensities. Rods were also capable of driving circadian photoentrainment at photopic intensities at which they were incapable of supporting a visually guided behavior. Using mice in which cone photoreceptors were ablated, we found that rods signal through cones at high light intensities, but not at low light intensities. Thus, rods use two distinct retinal circuits to drive ipRGC function to support circadian photoentrainment across a wide range of light intensities.

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Publication Date: 2010 Sep PMID: 20711183
Authors: Smith, S. L. - Hausser, M.
Journal: Nat Neurosci

Visual cortex shows smooth retinotopic organization on the macroscopic scale, but it is unknown how receptive fields are organized at the level of neighboring neurons. This information is crucial for discriminating among models of visual cortex. We used in vivo two-photon calcium imaging to independently map ON and OFF receptive field subregions of local populations of layer 2/3 neurons in mouse visual cortex. Receptive field subregions were often precisely shared among neighboring neurons. Furthermore, large subregions seem to be assembled from multiple smaller, non-overlapping subregions of other neurons in the same local population. These experiments provide, to our knowledge, the first characterization of the diversity of receptive fields in a dense local network of visual cortex and reveal elementary units of receptive field organization. Our results suggest that a limited pool of afferent receptive fields is available to a local population of neurons and reveal new organizational principles for the neural circuitry of the mouse visual cortex.

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Publication Date: 2010 Sep PMID: 20694004
Authors: Liu, K. - Lu, Y. - Lee, J. K. - Samara, R. - Willenberg, R. - Sears-Kraxberger, I. - Tedeschi, A. - Park, K. K. - Jin, D. - Cai, B. - Xu, B. - Connolly, L. - Steward, O. - Zheng, B. - He, Z.
Journal: Nat Neurosci

Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

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Publication Date: 2010 Sep PMID: 20694003
Authors: Smith-Hicks, C. - Xiao, B. - Deng, R. - Ji, Y. - Zhao, X. - Shepherd, J. D. - Posern, G. - Kuhl, D. - Huganir, R. L. - Ginty, D. D. - Worley, P. F. - Linden, D. J.
Journal: Nat Neurosci

It has been suggested that gene expression and protein synthesis are required for both long-term memory consolidation and late phases of long-term potentiation and long-term depression (LTD). The necessary genes and the specific transcription factor binding sites in their promoters remain unknown. We found that inhibition of the transcription factor SRF or its cofactor MAL blocked the late phase of LTD in mouse cultured cerebellar Purkinje cells, as did deletion of the immediate early gene Arc. Using neuronal bacterial artificial chromosome (BAC) transfection, we found that, in Arc(-/-) cells transfected with a wild-type Arc BAC, late-phase LTD was rescued. However, mutation of one SRF-binding site in the Arc promoter (SRE 6.9) blocked this rescue. Co-transfection of wild-type Arc and SRF engineered to bind mutated SRE 6.9 restored late-phase LTD in Arc(-/-), SRE 6.9 mutant BAC cells. Thus, SRF binding to SRE 6.9 in the Arc promoter is required for the late phase of cerebellar LTD.

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