Mutant disrupted-in-schizophrenia 1 in astrocytes: focus on glutamate metabolism
Document Type
Article
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.
Keywords
ASCT2, D-serine, NMDA, VGLUT, glutamate uptake, psychiatric disease
Medical Subject Headings
Animals; Animals, Newborn; Astrocytes (metabolism); Bromodeoxyuridine (metabolism); Cell Proliferation (genetics); Cells, Cultured; Glial Fibrillary Acidic Protein (genetics); Glutamate Carboxypeptidase II (metabolism); Glutamic Acid (metabolism); Glutaminase (metabolism); Hippocampus (metabolism); Membrane Proteins (genetics, metabolism); Mice; Mice, Transgenic; Mutation (genetics); Nerve Tissue Proteins (genetics, metabolism); Prosencephalon (cytology); Synaptosomes (metabolism); Vesicular Glutamate Transport Proteins (genetics, metabolism)
Publication Date
12-1-2014
Publication Title
Journal of neuroscience research
E-ISSN
1097-4547
Volume
92
Issue
12
First Page
1659
Last Page
68
PubMed ID
25131692
Digital Object Identifier (DOI)
10.1002/jnr.23459
Recommended Citation
Abazyan, Sofya; Yang, Eun Ju; Abazyan, Bagrat; Xia, Meng; Yang, Chunxia; Rojas, Camilo; Slusher, Barbara; Sattler, Rita; and Pletnikov, Mikhail, "Mutant disrupted-in-schizophrenia 1 in astrocytes: focus on glutamate metabolism" (2014). Translational Neuroscience. 1372.
https://scholar.barrowneuro.org/neurobiology/1372