Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia

Curley, A. A., Eggan, S. M., Lazarus, M. S., Huang, Z. J., Volk, D. W., Lewis, D. A. (2013) Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia. Neurobiology of Disease, 50 (1). pp. 179-186. ISSN 0969-9961

URL: http://www.ncbi.nlm.nih.gov/pubmed/23103418
DOI: 10.1016/j.nbd.2012.10.018

Abstract

Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PV(GAD67+/-)) or in all interneurons (GABA(GAD67+/-)) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PV(GAD67+/-) mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABA(GAD67+/-) mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell type-specificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > small molecules > GABA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
diseases & disorders > mental disorders
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neocortical interneurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neocortical interneurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neocortical interneurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > neocortical interneurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > neocortical interneurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > neocortical interneurons

diseases & disorders > mental disorders > schizophrenia
organism description > animal
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types

organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA dynamics
organism description > animal > mammal > rodent > mouse
CSHL Authors:
Communities: CSHL labs > Huang lab
Depositing User: Matt Covey
Date Deposited: 08 Feb 2013 17:39
Last Modified: 08 Feb 2013 17:39
PMCID: PMC3534919
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27240

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