Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia - PubMed (original) (raw)
Comparative Study
. 2011 May;21(5):999-1011.
doi: 10.1093/cercor/bhq169. Epub 2010 Sep 15.
Affiliations
- PMID: 20843900
- PMCID: PMC3077427
- DOI: 10.1093/cercor/bhq169
Comparative Study
Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia
Monica Beneyto et al. Cereb Cortex. 2011 May.
Abstract
Dysfunction of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia is associated with lamina-specific alterations in particular subpopulations of interneurons. In pyramidal cells, postsynaptic γ-aminobutyric acid (GABA(A)) receptors containing different α subunits are inserted preferentially in distinct subcellular locations targeted by inputs from specific interneuron subpopulations. We used in situ hybridization to quantify the laminar expression of α1, α2, α3, and α5 subunit, and of β1-3 subunit, mRNAs in the DLFPC of schizophrenia, and matched normal comparison subjects. In subjects with schizophrenia, mean GABA(A) α1 mRNA expression was 17% lower in layers 3 and 4, α2 expression was 14% higher in layer 2, α5 expression was 15% lower in layer 4, and α3 expression did not differ relative to comparison subjects. The mRNA expression of β2, which preferentially assembles with α1 subunits, was also 20% lower in layers 3 and 4, whereas β1 and β3 mRNA levels were not altered in schizophrenia. These expression differences were not attributable to medication effects or other potential confounds. These findings suggest that GABA neurotransmission in the DLPFC is altered at the postsynaptic level in a receptor subunit- and layer-specific manner in subjects with schizophrenia and support the hypothesis that GABA neurotransmission in this illness is predominantly impaired in certain cortical microcircuits.
Figures
Figure 1.
Representative autoradiograms illustrating expression of GABAA α1 (A), α2 (C), α3 (E), and α5 (G) subunits mRNA in DLPFC area 9 of a comparison subject (left) and a matched subject with schizophrenia (right). The density of hybridization signal is represented in pseudocolor according to the calibration scale (nCi/g) from the 14C standards. Solid and broken lines denote the pial surface and the gray matter–white matter border, respectively. The 6 cortical layers, identified by Nissl staining, are indicated on the left of each panel. Scale bar = 1 mm. Comparison of film autoradiogram OD measures for α1 (B), α2 (D), α3 (F), and α5 (H) in total gray matter of DLPFC in matched pairs of normal comparison subjects and subjects with schizophrenia (red circles) and schizoaffective disorder (open circles). Mean value for the group difference is indicated by the black square. Labels below the dashed unity line indicate pairs for which the subject with schizophrenia or schizoaffective disorder had a lower mean expression level than the matched comparison subject.
Figure 2.
Representative autoradiograms illustrating expression of GABAA β1 (A), β2 (C), and β3 (E) subunits mRNA in DLPFC area 9 of a comparison subject (left) and a matched subject with schizophrenia (right). For details, refer to Figure 1. Scale bar = 1 mm. Comparison of film autoradiogram OD measures for β1 (B), β2 (D), and β3 (F) in total gray matter of DLPFC in matched pairs of normal comparison subjects and subjects with schizophrenia (red circles) and schizoaffective disorder (open circles). For details, refer to Figure 1.
Figure 3.
Laminar expression of the mRNAs for GABAA receptor α1 (A, B), α2(C, D), α5 (E, F), and β2 (G, H) subunits. Left panels: Mean mRNA OD across cortical layers from the pial surface to the white matter border in schizophrenia (gray) and comparison groups (black). Right panels: Mean (SD) film OD for mRNA expression in each cortical layer between comparison and schizophrenia groups. *P< 0.1, **P < 0.05, ***P < 0.01.
Figure 4.
Cellular level analysis of the difference in GABAA subunits α1 and β2 mRNA expression in deep layer 3 of the DLPFC. Comparison of number of grains per cell measures for α1 (A, B) and β2 (C, D) in small (circles) (A, C) and large cells (triangles) (B, D) in matched pairs of normal comparison subjects and subjects with schizophrenia. Mean value for the group difference is indicated by the black square. The dashed unity line indicates no difference in expression levels.
Figure 5.
Schematic summary of hypothesized circuit-specific transcript alterations in pre- and postsynaptic markers of GABA neurotransmission in the DLPFC of subjects with schizophrenia. For each GABAA α subunit, the background shading marks the cortical layers where the indicated change in expression of that subunit was found. The laminar specificity of the decrease in α1 expression matches that of the alterations in GAD67 and PV mRNAs thought to be present in PV-positive basket cells. The increase in α2 expression in layer 2 is consistent with previous findings of pre- and postsynaptic alterations in chandelier cell inputs to the axon initial segment of pyramidal cells in this location. In contrast, the absence of alterations in α3 subunit expression, which is present postsynaptic to chandelier cells in deep layer pyramidal neurons matches the failure to find significant changes in chandelier cell inputs in these layers. The decrease in α5 was observed in deeper layers of DLPFC where the somata of pyramidal neurons whose apical dendrites are known to be innervated by SST+ Martinotti cells, also affected in schizophrenia, are predominantly located.
Similar articles
- Selective pyramidal cell reduction of GABA(A) receptor α1 subunit messenger RNA expression in schizophrenia.
Glausier JR, Lewis DA. Glausier JR, et al. Neuropsychopharmacology. 2011 Sep;36(10):2103-10. doi: 10.1038/npp.2011.102. Epub 2011 Jun 15. Neuropsychopharmacology. 2011. PMID: 21677653 Free PMC article. - Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia.
Hashimoto T, Arion D, Unger T, Maldonado-Avilés JG, Morris HM, Volk DW, Mirnics K, Lewis DA. Hashimoto T, et al. Mol Psychiatry. 2008 Feb;13(2):147-61. doi: 10.1038/sj.mp.4002011. Epub 2007 May 1. Mol Psychiatry. 2008. PMID: 17471287 Free PMC article. - Altered markers of tonic inhibition in the dorsolateral prefrontal cortex of subjects with schizophrenia.
Maldonado-Avilés JG, Curley AA, Hashimoto T, Morrow AL, Ramsey AJ, O'Donnell P, Volk DW, Lewis DA. Maldonado-Avilés JG, et al. Am J Psychiatry. 2009 Apr;166(4):450-9. doi: 10.1176/appi.ajp.2008.08101484. Epub 2009 Mar 16. Am J Psychiatry. 2009. PMID: 19289452 Free PMC article. - Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia.
Lewis DA, Hashimoto T, Morris HM. Lewis DA, et al. Neurotox Res. 2008 Oct;14(2-3):237-48. doi: 10.1007/BF03033813. Neurotox Res. 2008. PMID: 19073429 Free PMC article. Review. - [Schizophrenia and cortical GABA neurotransmission].
Hashimoto T, Matsubara T, Lewis DA. Hashimoto T, et al. Seishin Shinkeigaku Zasshi. 2010;112(5):439-52. Seishin Shinkeigaku Zasshi. 2010. PMID: 20560363 Review. Japanese.
Cited by
- GABAergic dysfunction in postmortem dorsolateral prefrontal cortex: implications for cognitive deficits in schizophrenia and affective disorders.
Hughes H, Brady LJ, Schoonover KE. Hughes H, et al. Front Cell Neurosci. 2024 Sep 24;18:1440834. doi: 10.3389/fncel.2024.1440834. eCollection 2024. Front Cell Neurosci. 2024. PMID: 39381500 Free PMC article. Review. - Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction.
Fournier LA, Phadke RA, Salgado M, Brack A, Nocon JC, Bolshakova S, Grant JR, Padró Luna NM, Sen K, Cruz-Martín A. Fournier LA, et al. iScience. 2024 Aug 30;27(9):110800. doi: 10.1016/j.isci.2024.110800. eCollection 2024 Sep 20. iScience. 2024. PMID: 39310747 Free PMC article. - The Pathophysiological Underpinnings of Gamma-Band Alterations in Psychiatric Disorders.
Palmisano A, Pandit S, Smeralda CL, Demchenko I, Rossi S, Battelli L, Rivolta D, Bhat V, Santarnecchi E. Palmisano A, et al. Life (Basel). 2024 Apr 30;14(5):578. doi: 10.3390/life14050578. Life (Basel). 2024. PMID: 38792599 Free PMC article. Review. - Altered excitatory and inhibitory ionotropic receptor subunit expression in the cortical visuospatial working memory network in schizophrenia.
Schoonover KE, Dienel SJ, Holly Bazmi H, Enwright JF 3rd, Lewis DA. Schoonover KE, et al. Neuropsychopharmacology. 2024 Jun;49(7):1183-1192. doi: 10.1038/s41386-024-01854-x. Epub 2024 Mar 28. Neuropsychopharmacology. 2024. PMID: 38548877 - Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction.
Fournier LA, Phadke RA, Salgado M, Brack A, Nocon JC, Bolshakova S, Grant JR, Padró Luna NM, Sen K, Cruz-Martín A. Fournier LA, et al. bioRxiv [Preprint]. 2024 Apr 12:2024.01.27.575409. doi: 10.1101/2024.01.27.575409. bioRxiv. 2024. PMID: 38328248 Free PMC article. Updated. Preprint.
References
- Akbarian S, Huntsman MM, Kim JJ, Tafazzoli A, Potkin SG, Bunney WE, Jr., Jones EG. GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls. Cereb Cortex. 1995a;5:550–560. - PubMed
- Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE, Jr., Jones EG. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry. 1995b;52:258–266. - PubMed
- Ali AB, Thomson AM. Synaptic alpha 5 subunit-containing GABAA receptors mediate IPSPs elicited by dendrite-preferring cells in rat neocortex. Cereb Cortex. 2008;18:1260–1271. - PubMed
- Bartos M, Vida I, Jonas P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci. 2007;8:45–56. - PubMed
- Benes FM, Davidson J, Bird ED. Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch Gen Psychiatry. 1986;43:31–35. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical