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Impairment of autophagic signaling in murine forebrain disrupts GABAA receptor trafficking leading to excitatoryinhibitory imbalance and ASD-like behaviours

Impairment of autophagic signaling in murine forebrain disru...

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中国神经科学学会第十二届全国学术会议

作者： Kelvin Hui noriko takashima Hiroshi Matsukawa Akiko Watanabe Per Nilsson Ryo Endo Takaomi Saido Shigeyoshi Itohara Takeo Yoshikawa Motomasa Tanaka Laboratory for Protein Conformation Diseases RIKEN Brain Science Institute Laboratory for Behavioral Genetics RIKEN Brain Science Institute Laboratory for Molecular Psychiatry RIKEN Brain Science Institute Laboroatory for Proteolytic Neuroscience RIKEN Brain Science Institute Department of Neurobiology Care Sciences and Society Karolinska Institutet

Many syndromic forms of autism spectrum disorder(ASD) are caused by mutations in proteins such as PTEN, TSC1, TSC2, and FMRP, which lie within the m TOR signaling pathway. While recent work has primarily focused on the dysregulation of protein translation via the deletion of these genes, few studies have examined how disruption of autophagy, another major downstream branch of m TOR signaling,contributes to neuronal dysfunction and ASD pathogenesis. To this end, we and others have previously examined mice deficient for autophagy in forebrain excitatory neurons via the deletion of Atg7 by Ca MKII-cre and observed ASD-like behavioural abnormalities in addition to neuronal dysfunctions from the molecular to the network level. As ASD is believed to be caused by an imbalance between excitatory and inhibitory signals in the brain, we have further extended our analysis to examine disruption of autophagy in forebrain GABAergic interneurons. Similar to disrupted autophagy in other neuronal and non-neuronal cell types, Atg7 deletion by Dlx5-cre results in time-dependent ubiquitin+ and p62+ aggregate formation in affected neurons. Notably, Dlx5-cre Atg7 c KO mice exhibit an overlapping set of ASD-like behavioural abnormalities previously observed in Ca MKII-cre Atg7 c KO animals. Furthermore, we have detected a disruption of the excitatory-inhibitory balance in both Ca MKII-cre and Dlx5-cre Atg7 c KO mice. Using primary cultured neurons, a specific reduction of surface GABAA receptors was observed in Atg7 c KO neurons. Unbiased mass spectrometric and subsequent antibody-based analyses demonstrated that members of the GABARAP(GABA receptor-associated protein) protein family accumulate and mislocalize to p62+ aggregates formed in affected neurons of both Ca MKII-cre and Dlx5-cre Atg7 c KO brains. Genetic manipulation of GABARAP family proteins and p62 in wild-type or Atg7 c KO neurons further revealed that GABAA receptor trafficking are influenced by p62 aggregates as they intera

关键词： autophagy autism protein aggregation GABAA receptors GABARAP

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