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Sci Adv. 2019 Apr 10;5(4):eaau8237. doi: 10.1126/sciadv.aau8237. eCollection 2019 Apr.

GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior.

Author information

1
Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan.
2
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan.
3
Laboratory for Synaptic Plasticity and Connectivity, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan.
4
Laboratory for Behavioral Genetics, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan.
5
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan.
6
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge 141 57, Sweden.

Abstract

Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted Atg7 in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to Atg7 deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2) to differentially form high-molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABAA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation.

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