Ulk2 controls cortical excitatory–inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons. (8th June 2018)

• Record Type: Journal Article
• Authors: Sumitomo, Akiko; Yukitake, Hiroshi; Hirai, Kazuko; Horike, Kouta; Ueta, Keisho; Chung, Youjin; Warabi, Eiji; Yanagawa, Toru; Kitaoka, Shiho; Furuyashiki, Tomoyuki; Narumiya, Shuh; Hirano, Tomoo; Niwa, Minae; Sibille, Etienne; Hikida, Takatoshi; Sakurai, Takeshi; Ishizuka, Koko; Sawa, Akira; Tomoda, Toshifumi
• Is Part Of: Human molecular genetics. Volume 27:Number 18(2018:Sep. 15)
• Page Start: 3165
• Page End: 3176
• Publication Date: 2018-06-08
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddy219
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: 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 GABAA 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 GABAA receptor-associated protein, a protein that regulates endocytic trafficking of GABAA receptors, also restored the GABAA 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 GABAA receptor surface presentation in pyramidal neurons.