Mutant disrupted-in-schizophrenia 1 in astrocytes: Focus on glutamate metabolism

Sofya Abazyan, Eun Ju Yang, Bagrat Abazyan, Meng Xia, Chunxia Yang, Camilo Rojas, Barbara Slusher, Rita Sattler, Mikhail Pletnikov

Research output: Contribution to journalArticle

Abstract

Disrupted-in-schizophrenia 1 (DISC1) is a genetic risk factor that has been implicated in major mental disorders. DISC1 binds to and stabilizes serine racemase to regulate production of D-serine by astrocytes, contributing to glutamate (GLU) neurotransmission. However, the possible involvement of astrocytic DISC1 in synthesis, metabolism, reuptake, or secretion of GLU remains unexplored. Therefore, we studied the effects of dominant-negative mutant DISC1 on various aspects of GLU metabolism by using primary astrocyte cultures and hippocampal tissue from transgenic mice with astrocyte-restricted expression of mutant DISC1. Although mutant DISC1 had no significant effects on astrocyte proliferation, GLU reuptake, glutaminase, or glutamate carboxypeptidase II activity, expression of mutant DISC1 was associated with increased levels of alanine-serine-cysteine transporter 2, vesicular glutamate transporters 1 and 3 in primary astrocytes and in the hippocampus, and elevated expression of the NR1 subunit and diminished expression of the NR2A subunit of N-methyl-D-aspartate (NMDA) receptors in the hippocampus, at postnatal day 21. Our findings indicate that decreased D-serine production by astrocytic mutant DISC1 might lead to compensatory changes in levels of the amino acid transporters and NMDA receptors in the context of tripartite synapse.

Original languageEnglish (US)
Pages (from-to)1659-1668
Number of pages10
JournalJournal of neuroscience research
Volume92
Issue number12
DOIs
StatePublished - Dec 1 2014

Keywords

  • ASCT2
  • D-serine
  • Glutamate uptake
  • NMDA
  • Psychiatric disease
  • VGLUT

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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