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

Kelvin K. Hui, Noriko Takashima, Akiko Watanabe, Thomas E. Chater, Hiroshi Matsukawa, Yoko Nekooki-Machida, Per Nilsson, Ryo Endo, Yukiko Goda, Takaomi C. Saido, Takeo Yoshikawa, Motomasa Tanaka

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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-Vassociated protein-like 2 (GABARAPL2) to differentially form high-Vmolecular 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.

Original languageEnglish (US)
Article numbereaau8237
JournalScience Advances
Volume5
Issue number4
DOIs
StatePublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • General

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