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

Hum Mol Genet. 2018 Sep 15;27(18):3165-3176. doi: 10.1093/hmg/ddy219.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autophagy / genetics*
  • DNA Copy Number Variations / genetics
  • Gene Expression Regulation / genetics
  • Humans
  • Mice
  • Peptides / genetics
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • Protein Transport / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology
  • Receptors, GABA-A / genetics
  • Schizophrenia / genetics*
  • Schizophrenia / physiopathology
  • Sequestosome-1 Protein / genetics*
  • Synaptic Transmission / genetics

Substances

  • Peptides
  • Receptors, GABA-A
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Ulk2 protein, mouse
  • Protein-Serine-Threonine Kinases