| RRC ID |
57548
|
| Author |
Hui KK, Takashima N, Watanabe A, Chater TE, Matsukawa H, Nekooki-Machida Y, Nilsson P, Endo R, Goda Y, Saido TC, Yoshikawa T, Tanaka M.
|
| Title |
GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior.
|
| Journal |
Sci Adv
|
| 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.
|
| Volume |
5(4)
|
| Pages |
eaau8237
|
| Published |
2019-4-1
|
| DOI |
10.1126/sciadv.aau8237
|
| PII |
aau8237
|
| PMID |
30989111
|
| PMC |
PMC6457945
|
| MeSH |
Animals
Apoptosis Regulatory Proteins / metabolism*
Autophagy*
Brain / pathology*
Humans
Interneurons / metabolism
Mice
Mice, Transgenic
Microtubule-Associated Proteins / metabolism*
Neurons / metabolism
Prosencephalon / physiology
Protein Aggregates
Protein Binding
Protein Transport
Receptors, GABA-A / metabolism*
Social Behavior*
|
| IF |
12.804
|
| Times Cited |
8
|
| Resource |
| DNA material |
CSII-CMV-MCS-IRES2-Venus (RDB04383)
pCAG-HIVgp (RDB04394) |
