Journal
SCIENCE ADVANCES
Volume 5, Issue 4, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aau8237
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Funding
- Japan Society for the Promotion of Science [26116044, JP18dm0107083]
- RIKEN Pioneering Projects, Cellular Evolution
- RIKEN Cellular Evolution project
- Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development [JP18H05435]
- RIKEN CBS/BSI internal funds
- Postdoctoral Fellowship Program for Foreign Researchers from Japan Society for the Promotion of Science [23-01512]
- RIKEN Foreign Postdoctoral Researcher program
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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 gamma-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 GABA(A) 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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