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      Excitatory synapses and gap junctions cooperate to improve Pv neuronal burst firing and cortical social cognition in Shank2-mutant mice

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          Abstract

          NMDA receptor (NMDAR) and GABA neuronal dysfunctions are observed in animal models of autism spectrum disorders, but how these dysfunctions impair social cognition and behavior remains unclear. We report here that NMDARs in cortical parvalbumin (Pv)-positive interneurons cooperate with gap junctions to promote high-frequency (>80 Hz) Pv neuronal burst firing and social cognition. Shank2 –/– mice, displaying improved sociability upon NMDAR activation, show impaired cortical social representation and inhibitory neuronal burst firing. Cortical Shank2 –/– Pv neurons show decreased NMDAR activity, which suppresses the cooperation between NMDARs and gap junctions (GJs) for normal burst firing. Shank2 –/– Pv neurons show compensatory increases in GJ activity that are not sufficient for social rescue. However, optogenetic boosting of Pv neuronal bursts, requiring GJs, rescues cortical social cognition in Shank2 –/– mice, similar to the NMDAR-dependent social rescue. Therefore, NMDARs and gap junctions cooperate to promote cortical Pv neuronal bursts and social cognition.

          Abstract

          How NMDAR and GABA neuronal dysfunctions result in impaired social behaviour is unclear. Here, the authors show that NMDARs and gap junctions in cortical PV interneurons modulate burst firing, affecting social behaviour.

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          Neocortical excitation/inhibition balance in information processing and social dysfunction.

          Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
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            Behavioural phenotyping assays for mouse models of autism.

            Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100-150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of autism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.
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              Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons.

              An understanding of the diversity of cortical GABAergic interneurons is critical to understand the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+-binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for ∼40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents ∼30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layerIV. The 5HT3aR group, which also accounts for ∼30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that do not express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests that they might be involved in shaping cortical circuits during specific brain states and behavioral contexts. Copyright © 2010 Wiley Periodicals, Inc.
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                Author and article information

                Contributors
                joominp@ibs.re.kr
                mwjung@kaist.ac.kr
                sbpaik@kaist.ac.kr
                kime@kaist.ac.kr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                25 August 2021
                25 August 2021
                2021
                : 12
                : 5116
                Affiliations
                [1 ]GRID grid.410720.0, ISNI 0000 0004 1784 4496, Center for Synaptic Brain Dysfunctions, , Institute for Basic Science (IBS), ; Daejeon, Korea
                [2 ]GRID grid.15444.30, ISNI 0000 0004 0470 5454, Department of Anatomy, College of Medicine, , Yonsei University, ; Seoul, Korea
                [3 ]GRID grid.37172.30, ISNI 0000 0001 2292 0500, Department of Biological Sciences, KAIST, ; Daejeon, Korea
                [4 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Brain and Cognitive Science, College of Natural Science, , Seoul National University, ; Seoul, Korea
                [5 ]GRID grid.410720.0, ISNI 0000 0004 1784 4496, Center for Cognition and Sociality, , Institute for Basic Science (IBS), ; Daejeon, Korea
                [6 ]GRID grid.37172.30, ISNI 0000 0001 2292 0500, Program of Brain and Cognitive Engineering, Department of Bio and Brain Engineering, , Korea Advanced Institute for Science and Technology (KAIST), ; Daejeon, Korea
                [7 ]GRID grid.35541.36, ISNI 0000000121053345, Center for BioMicrosystems, Brain Science Institute, , Korea Institute of Science and Technology (KIST), ; Seoul, Korea
                [8 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Bioengineering, Department of Psychiatry and Behavioral Sciences, Howard Hughes Medical Institute, , Stanford University, ; Stanford, CA USA
                [9 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Physiology, College of Medicine, , Seoul National University, ; Seoul, Korea
                Author information
                http://orcid.org/0000-0001-9726-4819
                http://orcid.org/0000-0003-3644-2516
                http://orcid.org/0000-0002-5956-9985
                http://orcid.org/0000-0003-2426-2470
                http://orcid.org/0000-0001-8280-2717
                http://orcid.org/0000-0001-9016-6749
                http://orcid.org/0000-0001-9440-3967
                http://orcid.org/0000-0002-4145-600X
                http://orcid.org/0000-0002-4078-305X
                http://orcid.org/0000-0001-5518-6584
                Article
                25356
                10.1038/s41467-021-25356-2
                8387434
                34433814
                4fd46652-30cf-4625-ab7c-670b726ccf5d
                © The Author(s) 2021

                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
                : 20 December 2020
                : 5 August 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003725, National Research Foundation of Korea (NRF);
                Award ID: IBS-R002-D1
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Uncategorized
                autism spectrum disorders,social behaviour,gap junctions,neurotransmitters
                Uncategorized
                autism spectrum disorders, social behaviour, gap junctions, neurotransmitters

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