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.

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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.

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Figures

Figure 1.

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.

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.

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.

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.

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.

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