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      Common circuit defect of excitatory-inhibitory balance in mouse models of autism

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          Abstract

          One unifying explanation for the complexity of Autism Spectrum Disorders (ASD) may lie in the disruption of excitatory/inhibitory (E/I) circuit balance during critical periods of development. We examined whether Parvalbumin (PV)-positive inhibitory neurons, which normally drive experience-dependent circuit refinement (Hensch Nat Rev Neurosci 6:877–888, 1), are disrupted across heterogeneous ASD mouse models. We performed a meta-analysis of PV expression in previously published ASD mouse models and analyzed two additional models, reflecting an embryonic chemical insult (prenatal valproate, VPA) or single-gene mutation identified in human patients (Neuroligin-3, NL-3 R451C). PV-cells were reduced in the neocortex across multiple ASD mouse models. In striking contrast to controls, both VPA and NL-3 mouse models exhibited an asymmetric PV-cell reduction across hemispheres in parietal and occipital cortices (but not the underlying area CA1). ASD mouse models may share a PV-circuit disruption, providing new insight into circuit development and potential prevention by treatment of autism.

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          The online version of this article (doi:10.1007/s11689-009-9023-x) contains supplementary material, which is available to authorized users.

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          Cortical inhibitory neurons and schizophrenia.

          Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
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            Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks.

            Gamma frequency oscillations are thought to provide a temporal structure for information processing in the brain. They contribute to cognitive functions, such as memory formation and sensory processing, and are disturbed in some psychiatric disorders. Fast-spiking, parvalbumin-expressing, soma-inhibiting interneurons have a key role in the generation of these oscillations. Experimental analysis in the hippocampus and the neocortex reveals that synapses among these interneurons are highly specialized. Computational analysis further suggests that synaptic specialization turns interneuron networks into robust gamma frequency oscillators.
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              Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.

              Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
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                Author and article information

                Contributors
                +1-617-9194650 , +1-617-9192430 , michela.fagiolini@childrens.harvard.edu
                +1-617-9194650 , +1-617-9192430 , hensch@mcb.harvard.edu
                Journal
                J Neurodev Disord
                Journal of neurodevelopmental disorders
                Springer US (Boston )
                1866-1947
                1866-1955
                11 July 2009
                June 2009
                : 1
                : 2
                : 172-181
                Affiliations
                [1 ]Center for Brain Science, Dept. Molecular & Cellular Biology, Harvard University, 52 Oxford St., Cambridge, MA 02138 USA
                [2 ]FM Kirby Neurobiology Center, Dept. Neurology, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115 USA
                [3 ]HHMI, Stanford School of Medicine, 1050 Arastradero Road (B249F), Palo Alto, CA 94304 USA
                Article
                9023
                10.1007/s11689-009-9023-x
                2906812
                20664807
                © Springer Science+Business Media, LLC 2009
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                © Springer Science+Business Media, LLC 2009

                Neurosciences

                neuroligin, parvalbumin, vpa, gaba

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