title: Mutant disrupted-in-schizophrenia 1 in astrocytes: focus on glutamate metabolism.
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.
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sofya
authors.initials: S
authors.lastname: Abazyan
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Yang
authors.forename: Bagrat
authors.initials: B
authors.lastname: Abazyan
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.forename: Chunxia
authors.initials: C
authors.lastname: Yang
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Barbara
authors.initials: B
authors.lastname: Slusher
authors.forename: Rita
authors.initials: R
authors.lastname: Sattler
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pletnikov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology; D013574:Synaptosomes / Q000378:metabolism; D050496:Vesicular Glutamate Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C498794:Disc1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid; D043425:Glutamate Carboxypeptidase II; D005972:Glutaminase; D001973:Bromodeoxyuridine
keywords: ASCT2; D-serine; NMDA; VGLUT; glutamate uptake; psychiatric disease