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      Downregulation of Npas4 in parvalbumin interneurons and cognitive deficits after neonatal NMDA receptor blockade: relevance for schizophrenia

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          Abstract

          Dysfunction of prefrontal parvalbumin (PV+) interneurons has been linked with severe cognitive deficits as observed in several neurodevelopmental disorders including schizophrenia. However, whether a specific aspect of PV+ neurons deregulation, or a specific molecular mechanism within PV+ neurons is responsible for cognitive deficits and other behavioral impairments remain to be determined. Here, we induced cognitive deficits and altered the prefrontal PV system in mice by exposing them neonatally to the NMDA receptor antagonist ketamine. We observed that the cognitive deficits and hyperactivity induced by neonatal ketamine were associated with a downregulation of Npas4 expression specifically in PV+ neurons. To determine whether Npas4 downregulation-induced dysfunction of PV+ neurons could be a molecular contributor to the cognitive and behavioral impairments reported after neonatal ketamine, we used a transgenic Cre-Lox approach. Reduced Npas4 expression within PV+ neurons replicates deficits in short-term memory observed after neonatal ketamine, but does not reproduce disturbances in general activity. Our data show for the first time that the brain-specific transcription factor Npas4 may be an important contributor to PV+ neurons dysfunction in neurodevelopmental disorders, and thereby could contribute to the cognitive deficits observed in diseases characterized by abnormal functioning of PV+ neurons such as schizophrenia. These findings provide a potential novel therapeutic target to rescue the cognitive impairments of schizophrenia that remain to date unresponsive to treatments.

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          Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia.

          Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and postsynaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Social cognition in schizophrenia.

            Individuals with schizophrenia exhibit impaired social cognition, which manifests as difficulties in identifying emotions, feeing connected to others, inferring people's thoughts and reacting emotionally to others. These social cognitive impairments interfere with social connections and are strong determinants of the degree of impaired daily functioning in such individuals. Here, we review recent findings from the fields of social cognition and social neuroscience and identify the social processes that are impaired in schizophrenia. We also consider empathy as an example of a complex social cognitive function that integrates several social processes and is impaired in schizophrenia. This information may guide interventions to improve social cognition in patients with this disorder.
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              Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.

              Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.
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                Author and article information

                Contributors
                coutellier.8@osu.edu
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                21 February 2019
                21 February 2019
                2019
                : 9
                : 99
                Affiliations
                [1 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Department of Psychology, , The Ohio State University, ; 225 Psychology Building, 1835 Neil Avenue, Columbus, Ohio 43210 USA
                [2 ]ISNI 0000 0001 1545 0811, GRID grid.412332.5, Department of Neuroscience, The Ohio State University, , Wexner Medical Center, ; 333W. 10th Ave, Columbus, OH 43210 USA
                [3 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Present Address: Moores Cancer Center, , University California, San Diego, ; 3855 Health Sciences Dr, La Jolla, CA 92093 USA
                [4 ]ISNI 0000 0004 1936 8294, GRID grid.214572.7, Present Address: Interdisciplinary Graduate Program in Neuroscience, , University of Iowa, ; Iowa City, IA 52242 USA
                Article
                436
                10.1038/s41398-019-0436-3
                6385315
                30792384
                b6d119eb-6374-49fa-9711-b820ecd808e4
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 June 2018
                : 29 January 2019
                : 12 February 2019
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                © The Author(s) 2019

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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