期刊
HUMAN MOLECULAR GENETICS
卷 27, 期 18, 页码 3165-3176出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy219
关键词
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资金
- National Iinstitutes of Health [MH-084018, MH-094268, MH-069853, MH-085226, MH-088753, MH-092443, MH105660]
- Stanley Foundation
- S-R Foundation
- RUSK Foundation
- NARSAD
- Maryland Stem Cell Research Fund
- Department of Defense/Congressionally Directed Medical Research Program [W81XWH-11-1-0269]
- Childrends Tumor Foundation-Drug Discovery Initiative
- Japan Society of Promotion of Science [49170001, 24689015, 25110717, 15H04259, 15H01285, 16K01948, 15H04275, 16H06568, 16K14579]
- Takeda Science Foundation
- Naito Foundation
- Kato Memorial Trust for Nambyo Research
- International Cooperative Research Program of Institute for Protein Research at Osaka University [ICRa-1713]
- Takeda Pharmaceutical Co. Ltd.
- Grants-in-Aid for Scientific Research [15H01285, 15H04259, 16K01948, 16K14579, 16H06568, 25110717, 24689015, 15H04275] Funding Source: KAKEN
Autophagy plays an essential role in intracellular degradation and maintenance of cellular homeostasis in all cells, including neurons. Although a recent study reported a copy number variation of Ulk2, a gene essential for initiating autophagy, associated with a case of schizophrenia (SZ), it remains to be studied whether Ulk2 dysfunction could underlie the pathophysiology of the disease. Here we show that Ulk2 heterozygous (Ulk2(+/-)) mice have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, predominantly in pyramidal neurons of the prefrontal cortex (PFC), and exhibit behavioral deficits associated with the PFC functions, including attenuated sensorimotor gating and impaired cognition. Ulk2(+/-) neurons showed imbalanced excitatory-inhibitory neurotransmission, due in part to selective down-modulation of gamma-aminobutyric acid (GABA)(A) receptor surface expression in pyramidal neurons. Genetically reducing p62 gene dosage or suppressing p62 protein levels with an autophagy-inducing agent restored the GABA(A) receptor surface expression and rescued the behavioral deficits in Ulk2(+/-) mice. Moreover, expressing a short peptide that specifically interferes with the interaction of p62 and GABA(A) receptor-associated protein, a protein that regulates endocytic trafficking of GABA(A) receptors, also restored the GABA(A) receptor surface expression and rescued the behavioral deficits in Ulk2(+/-) mice. Thus, the current study reveals a novel mechanism linking deregulated autophagy to functional disturbances of the nervous system relevant to SZ, through regulation of GABA(A) receptor surface presentation in pyramidal neurons.
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