Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia

Abstract

Objective: Individuals with schizophrenia exhibit disturbances in a number of cognitive, affective, sensory, and motor functions that depend on the circuitry of different cortical areas. The cognitive deficits associated with dysfunction of the dorsolateral prefrontal cortex result, at least in part, from abnormalities in GABA neurotransmission, as reflected in a specific pattern of altered expression of GABA-related genes. Consequently, the authors sought to determine whether this pattern of altered gene expression is restricted to the dorsolateral prefrontal cortex or could also contribute to the dysfunction of other cortical areas in subjects with schizophrenia.

Method: Real-time quantitative polymerase chain reaction was used to assess the levels of eight GABA-related transcripts in four cortical areas (dorsolateral prefrontal cortex, anterior cingulate cortex, and primary motor and primary visual cortices) of subjects (N=12) with schizophrenia and matched normal comparison subjects.

Results: Expression levels of seven transcripts were lower in subjects with schizophrenia, with the magnitude of reduction for each transcript comparable across the four areas. The largest reductions were detected for mRNA encoding somatostatin and parvalbumin, followed by moderate decreases in mRNA expression for the 67-kilodalton isoform of glutamic acid decarboxylase, the GABA membrane transporter GAT-1, and the alpha 1 and delta subunits of GABA(A) receptors. In contrast, the expression of calretinin mRNA did not differ between the subject groups in any of the four areas.

Conclusions: Because the areas examined represent the major functional domains (e.g., association, limbic, motor, and sensory) of the cerebral cortex, our findings suggest that a conserved set of molecular alterations affecting GABA neurotransmission contribute to the pathophysiology of different clinical features of schizophrenia.

FIGURE 1. Locations of Cortical Gray Matter Excision for the Purpose of RNA Extraction^a

^aAs shown in coronal sections through the right hemisphere of the human brain. Approximate locations where cortical gray matter was excised are in red.

FIGURE 2. GABA-Related Transcript Expression Levels Across the Four Cortical Areas of Subjects With Schizophrenia and Matched Normal Comparison Subjects^a

^aExpression levels of each GABA-related transcript were determined as ratios to the geometric mean of the three most stable control transcript (beta-actin, cyclophilin A, and glyceraldehyde-3-phosphate dehydrogenase). ^bSignificant effect of diagnosis only (F=18, df=1, 6.5, p=0.005). ^cSignificant effect of diagnosis (F=36, df=1, 9.1, p<0.001) and area (F=130, df=3, 6.5, p<0.001). ^dSignificant effect of diagnosis (F=8.3, df=1, 9.2, p=0.018) and area (F=220, df=3, 5.5, p<0.001).

FIGURE 3. Summary of Differences in GABA-Related Transcript Expression in Subjects With Schizophrenia Across the Four Cortical Areas^a

^aDifferences in expression within each subject pair for each transcript are plotted as log2-transformed ratios of schizophrenia subjects to normal comparison subjects. Corresponding nontransformed schizophrenia/normal comparison expression ratios are shown on the right axis. Horizontal bars indicate the mean for all subject pairs in each cortical area. ^bSignificant effect of diagnosis only for GAD₆₇ (F=18, df=1, 6.5, p=0.005) and both diagnosis (F=11, df=1, 11, p=0.008) and area (F=20, df=3, 9.4, p<0.001) for GAD₆₅. ^cSignificant effect of both diagnosis (F=4.9, df=1, 11, p=0.048) and area (F=15, df=3, 11, p<0.001). ^dSignificant effect of both diagnosis (F=21, df=1, 7.6, p=0.002) and area (F=870, df=3, 6.5, p<0.001). ^eSignificant effect of both diagnosis (F=36, df=1, 9.1, p<0.001) and area (F=130, df=3, 6.5, p<0.001). ^fSignificant effect of area only (F=150, df=3, 9, p<0.001). ^gSignificant effect of both diagnosis and area for GABA_A receptor α1 subunit (F=8.3, df=1, 9.2, p=0.018; F=220, df=3, 5.5, p<0.001, respectively) and δ subunit (F=14, df=1, 6.5, p=0.008; F=113, df=3, 7.6, p<0.001, respectively).

FIGURE 4. Rank-Order by Magnitude of Change in GABA-Related Transcript Expression Across Cortical Areas^a

^aA) Eight GABA-related transcripts rank-ordered by the magnitude of difference in their expression for each cortical area. B) Spearman's rankorder correlation coefficients calculated between the rank-orders of any given two cortical areas.