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      Alterations of Electrophysiological Properties and Ion Channel Expression in Prefrontal Cortex of a Mouse Model of Schizophrenia

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Maternal immune activation (MIA) and juvenile social isolation (SI) are two most prevalent and widely accepted environmental insults that could increase the propensity of psychiatric illnesses. Using a two-hit mouse model, we examined the impact of the combination of these two factors on animal behaviors, neuronal excitability and expressions of voltage-gated sodium (Nav) and small conductance calcium-activated potassium (SK) channels in the prefrontal cortex (PFC). We found that MIA-SI induced a number of schizophrenia-related behavioral deficits. Patch clamp recordings revealed alterations in electrophysiological properties of PFC layer-5 pyramidal cells, including hyperpolarized resting membrane potential (RMP), increased input resistance and enhanced medium after-hyperpolarization (mAHP). MIA-SI also increased the ratio of the maximal slope of somatodendritic potential to the peak slope of action potential upstroke, indicating a change in perisomatic Nav availability. Consistently, MIA-SI significantly increased the expression level of Nav1.2 and SK3 channels that contribute to the somatodendritic potential and the mAHP, respectively. Together, these changes may alter neuronal signaling in the PFC and behavioral states, representing a molecular imprint of environmental insults associated with neuropsychiatric illnesses.

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          Most cited references 51

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          Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice.

          Deficits in social interaction are important early markers for autism and related neurodevelopmental disorders with strong genetic components. Standardized behavioral assays that measure the preference of mice for initiating social interactions with novel conspecifics would be of great value for mutant mouse models of autism. We developed a new procedure to assess sociability and the preference for social novelty in mice. To quantitate sociability, each mouse was scored on measures of exploration in a central habituated area, a side chamber containing an unfamiliar conspecific (stranger 1) in a wire cage, or an empty side chamber. In a secondary test, preference for social novelty was quantitated by presenting the test mouse with a choice between the first, now-familiar, conspecific (stranger 1) in one side chamber, and a second unfamiliar mouse (stranger 2) in the other side chamber. Parameters scored included time spent in each chamber and number of entries into the chambers. Five inbred strains of mice were tested, C57BL/6J, DBA/2J, FVB/NJ, A/J and B6129PF2/J hybrids. Four strains showed significant levels of sociability (spend- ing more time in the chamber containing stranger 1 than in the empty chamber) and a preference for social novelty (spending more time in the chamber containing stranger 2 than in the chamber containing the now-familiar stranger 1). These social preferences were observed in both male and female mice, and in juveniles and adults. The exception was A/J, a strain that demonstrated a preference for the central chamber. Results are discussed in terms of potential applications of the new methods, and the proper controls for the interpretation of social behavior data, including assays for health, relevant sensory abilities and motor functions. This new standardized procedure to quantitate sociability and preference for social novelty in mice provides a method to assess tendencies for social avoidance in mouse models of autism.
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            Schizophrenia

            Summary Schizophrenia is a complex, heterogeneous behavioural and cognitive syndrome whose origins appear to lie in genetic and/or environmental disruption of brain development. Dysfunction of dopaminergic neurotransmission appears to contribute to the genesis of psychotic symptoms but the evidence also points to a more widespread and variable involvement of brain areas and circuits. There is emerging evidence that disturbances of synaptic function might underlie abnormalities of neuronal connectivity possibly involving interneurons, but the precise nature, location and timing of these events is uncertain. Current treatment consists largely in the administration of antipsychotic drugs combined with psychological therapies, social support and rehabilitation, but there is a pressing need for more effective treatments and for services to be delivered more effectively. Progress in understanding the disorder has been great in recent years with advances in genomics, epidemiology and neuroscience, and the opportunities for further scientific advance are great: but so are the challenges.
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              A critical period for social experience-dependent oligodendrocyte maturation and myelination.

              Early social isolation results in adult behavioral and cognitive dysfunction that correlates with white matter alterations. However, how social deprivation influences myelination and the significance of these myelin defects in the adult remained undefined. We show that mice isolated for 2 weeks immediately after weaning have alterations in prefrontal cortex function and myelination that do not recover with reintroduction into a social environment. These alterations, which occur only during this critical period, are phenocopied by loss of oligodendrocyte ErbB3 receptors, and social isolation leads to reduced expression of the ErbB3 ligand neuregulin-1. These findings indicate that social experience regulates prefrontal cortex myelination through neuregulin-1/ErbB3 signaling and that this is essential for normal cognitive function, thus providing a cellular and molecular context to understand the consequences of social isolation.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                17 December 2019
                2019
                : 13
                Affiliations
                1State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University , Beijing, China
                2IDG/McGovern Institute for Brain Research, Beijing Normal University , Beijing, China
                Author notes

                Edited by: Marie-Eve Tremblay, Laval University, Canada

                Reviewed by: Darrin Brager, The University of Texas at Austin, United States; Wen-Jun Gao, Drexel University, United States

                *Correspondence: Yousheng Shu, yousheng@ 123456bnu.edu.cn

                This article was submitted to Cellular Neuropathology, a section of the journal Frontiers in Cellular Neuroscience

                Article
                10.3389/fncel.2019.00554
                6927988
                Copyright © 2019 Mi, Yang, He, Zhang, Xiao and Shu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 3, Tables: 1, Equations: 1, References: 51, Pages: 11, Words: 0
                Categories
                Neuroscience
                Original Research

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