Ulk2 controls cortical excitatory-inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons

Academic Article

Abstract

  • © The Author(s) 2018. 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.
  • Authors

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    Digital Object Identifier (doi)

    Author List

  • Sumitomo A; Yukitake H; Hirai K; Horike K; Ueta K; Chung Y; Warabi E; Yanagawa T; Kitaoka S; Furuyashiki T
  • Start Page

  • 3165
  • End Page

  • 3176
  • Volume

  • 27
  • Issue

  • 18