TY - JOUR
T1 - GABAA receptor subunit gene expression in human prefrontal cortex
T2 - Comparison of schizophrenics and controls
AU - Akbarian, Schahram
AU - Huntsman, Molly M.
AU - Kim, James J.
AU - Tafazzoli, Alireza
AU - Potkin, Steven G.
AU - Bunney, William E.
AU - Jones, Edward G.
N1 - Funding Information:
We thank Dr. C. Sandman and Dr. B. Hcttrick for assistance in the statistical analysis, Ms. Hao Truong, Mr. Phong Nguyen, and Ms. Amy Wu for technical help and the patients and families who participated in this study. This work was supported by Grant Number MH 44188 from the National Institute of Mental Health and by Human Brain Project Grant Number MH/DA 52154, which is funded joindy by the National Institute of Mental Health, the National Institute on Drug Abuse, and the National Aeronautics and Space Administration. Funding also was provided by awards from the Stanley Foundation and the National Alliance for Research on Schizophrenia and Depression (NARSAD). Resources for brain processing were provided by Dr. W. W. Tourtellotte and Ms. Iris Rosario at the National Neurological Research Specimen Bank at the VA Wadsworth Medical Center, Los Angeles, CA 90073.
PY - 1995/11
Y1 - 1995/11
N2 - The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation.In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (α1, α2, α5, β1, β2, γ2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitomotry.Three types of laminar expression pattern were observed: mRNAs for the α1, β2 and γ2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the α2, α5, and β1 subunits were expressed at lower levels; α2 and β1 were expressed predominantly by cells in layers II, III, and IV; α5 was expressed predominantly in layers IV, V, and Vl. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls.Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of schizophrenics, the previously reported upregulation of muscimol binding sites and downregulation of benzodiazepine binding sites in the prefrontal and adjacent cingulate cortex of schizophrenics are possibly due to posttranscriptional modifications of mRNAs and their translated polypeptides.
AB - The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation.In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (α1, α2, α5, β1, β2, γ2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitomotry.Three types of laminar expression pattern were observed: mRNAs for the α1, β2 and γ2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the α2, α5, and β1 subunits were expressed at lower levels; α2 and β1 were expressed predominantly by cells in layers II, III, and IV; α5 was expressed predominantly in layers IV, V, and Vl. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls.Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of schizophrenics, the previously reported upregulation of muscimol binding sites and downregulation of benzodiazepine binding sites in the prefrontal and adjacent cingulate cortex of schizophrenics are possibly due to posttranscriptional modifications of mRNAs and their translated polypeptides.
UR - https://www.scopus.com/pages/publications/0028971245
U2 - 10.1093/cercor/5.6.550
DO - 10.1093/cercor/5.6.550
M3 - Article
C2 - 8590827
AN - SCOPUS:0028971245
SN - 1047-3211
VL - 5
SP - 550
EP - 560
JO - Cerebral Cortex
JF - Cerebral Cortex
IS - 6
ER -