Striatal N-Acetylaspartate Synthetase Shati/Nat8l Regulates Depression-Like Behaviors via mGluR3-Mediated Serotonergic Suppression in Mice

Int J Neuropsychopharmacol. 2017 Dec 1;20(12):1027-1035. doi: 10.1093/ijnp/pyx078.

Abstract

Background: Several clinical studies have suggested that N-acetylaspartate and N-acetylaspartylglutamate levels in the human brain are associated with various psychiatric disorders, including major depressive disorder. We have previously identified Shati/Nat8l, an N-acetyltransferase, in the brain using an animal model of psychosis. Shati/Nat8l synthesizes N-acetylaspartate from L-aspartate and acetyl-coenzyme A. Further, N-acetylaspartate is converted into N-acetylaspartylglutamate, a neurotransmitter for metabotropic glutamate receptor 3.

Methods: Because Shati/Nat8l mRNA levels were increased in the dorsal striatum of mice following the exposure to forced swimming stress, Shati/Nat8l was overexpressed in mice by the microinjection of adeno-associated virus vectors containing Shati/Nat8l gene into the dorsal striatum (dS-Shati/Nat8l mice). The dS-Shati/Nat8l mice were further assessed using behavioral and neurochemical tests.

Results: The dS-Shati/Nat8l mice exhibited behavioral despair in the forced swimming and tail suspension tests and social withdrawal in the 3-chamber social interaction test. These depression-like behaviors were attenuated by the administration of a metabotropic glutamate receptor 2/3 antagonist and a selective serotonin reuptake inhibitor. Furthermore, the metabolism of N-acetylaspartate to N-acetylaspartylglutamate was decreased in the dorsal striatum of the dS-Shati/Nat8l mice. This finding corresponded with the increased expression of glutamate carboxypeptidase II, an enzyme that metabolizes N-acetylaspartylglutamate present in the extracellular space. Extracellular serotonin levels were lower in the dorsal striatum of the dS-Shati/Nat8l and normal mice that were repeatedly administered a selective glutamate carboxypeptidase II inhibitor.

Conclusions: Our findings indicate that the striatal expression of N-acetylaspartate synthetase Shati/Nat8l plays a role in major depressive disorder via the metabotropic glutamate receptor 3-mediated functional control of the serotonergic neuronal system.

Keywords: Shati/Nat8l; behavioral despair; mGluR3; serotonin; social withdrawal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism
  • Animals
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / metabolism
  • Corpus Striatum / metabolism*
  • Depression / genetics*
  • Depression / metabolism
  • Depression / pathology*
  • Dipeptides / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation / genetics*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Hindlimb Suspension
  • Humans
  • Interpersonal Relations
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microdialysis
  • Microinjections
  • Receptors, Metabotropic Glutamate / metabolism*
  • Serotonin / metabolism*
  • Swimming / psychology
  • Transduction, Genetic

Substances

  • Dipeptides
  • MRAP protein, human
  • Membrane Proteins
  • Receptors, Metabotropic Glutamate
  • enhanced green fluorescent protein
  • metabotropic glutamate receptor 3
  • Green Fluorescent Proteins
  • isospaglumic acid
  • Aspartic Acid
  • Serotonin
  • N-acetylaspartate
  • Acetyltransferases
  • Shati protein, mouse