TY - JOUR
T1 - Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia
AU - Hashimoto, T.
AU - Arion, D.
AU - Unger, T.
AU - Maldonado-Avilés, J. G.
AU - Morris, H. M.
AU - Volk, D. W.
AU - Mirnics, K.
AU - Lewis, D. A.
N1 - Funding Information:
This work was supported by NIH grants MH43784 (DAL), MH45156 (DAL), MH067234 (KM) and MH070786 (KM), by an investigator-initiated grant from Eli Lilly (DAL) and by a NARSAD Young Investigator Award (TH). We thank Ms Mary L Brady and Ms Jimette Gilmartin for their assistance in preparing figures and the manuscript.
PY - 2008/2
Y1 - 2008/2
N2 - In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in γ-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD 67) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABAA receptor subunits (α1, α4, β3, γ2 and δ). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD67, SST and α1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABAA receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.
AB - In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in γ-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD 67) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABAA receptor subunits (α1, α4, β3, γ2 and δ). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD67, SST and α1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABAA receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.
KW - GABA receptor
KW - GAD
KW - In situ hybridization
KW - Microarray
KW - Neuropeptides
KW - Quantitative PCR
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U2 - 10.1038/sj.mp.4002011
DO - 10.1038/sj.mp.4002011
M3 - Article
C2 - 17471287
AN - SCOPUS:38349091354
SN - 1359-4184
VL - 13
SP - 147
EP - 161
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 2
ER -