GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior
KK Hui, N Takashima, A Watanabe, TE Chater… - Science …, 2019 - science.org
KK Hui, N Takashima, A Watanabe, TE Chater, H Matsukawa, Y Nekooki-Machida…
Science advances, 2019•science.orgDysfunctional 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 …
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 …
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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