Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia

Abstract

The underlying pathology of schizophrenia (SZ) is likely as heterogeneous as its symptomatology. A variety of cortical and subcortical regions, including the prefrontal cortex, have been implicated in its pathology, and a number of genes have been identified as risk factors for disease development. We used in situ hybridization (ISH) to examine the expression of 58 genes in the dorsolateral prefrontal cortex (DLPFC, comprised of Brodmann areas 9 and 46) from 19 individuals with a premorbid diagnosis of SZ and 33 control individuals. Genes were selected based on: (1) previous identification as risk factors for SZ; (2) cell type markers or (3) laminar markers. Cell density and staining intensity were compared in the DLPFC, as well as separately in Brodmann areas 9 and 46. The expression patterns of a variety of genes, many of which are associated with the GABAergic system, were altered in SZ when compared with controls. Additional genes, including C8orf79 and NR4A2, showed alterations in cell density or staining intensity between the groups, highlighting the need for additional studies. Alterations were, with only a few exceptions, limited to Brodmann area 9, suggesting regional specificity of pathology in the DLPFC. Our results agree with previous studies on the GABAergic involvement in SZ, and suggest that areas 9 and 46 may be differentially affected in the disease. This study also highlights additional genes that may be altered in SZ, and indicates that these potentially interesting genes can be identified by ISH and high-throughput image analysis techniques.

Figure 1

(a–d) P-value charts for cell density (a), and staining intensity of SZ-associated genes (c). Genes are listed across the top of the graph, while the areas analyzed and their respective layers are on the left. Corrected P-values are denoted by color for each layer as shown in the color key between the two images. Black, NS. (b) Cell density measurements by layer for CHRNA7 in the DLPFC. (d) Staining intensity measurements for AKT1 in the DLPFC. Controls: black bars; SZ: gray bars. Bars represent mean values±s.e.m. for each layer. *P<0.05; **P<0.01.

Figure 2

P-value charts for cell density (a), and staining intensity (c) of interneuron marker genes. Genes are listed across the top of the graph (SZ-associated genes are in blue), whereas the areas analyzed and their respective layers are on the left. Corrected P-values are denoted by color for each layer as shown in the color key between the two charts. Black, NS. (b) Cortical expression pattern for the cell density of interneuron markers in the DLPFC for the five interneuron markers that showed significant differences. Black lines: control values; blue lines: SZ subjects.

Figure 3

(a–d) P-value charts for cell density and staining intensity of laminar marker genes. No significant differences were found in area 46. Genes are listed across the top of the graph (SZ-associated genes are in blue), with genes that are preferentially expressed in layer 1 to the left, and those preferentially expressed in layer 6 to the right. The areas analyzed and their respective layers are on the left. Corrected P-values are denoted by color for each layer as shown in the color key between the charts. Black, NS.

Figure 4

The decrease in the density of cells stained for CALB2 in area 9 is apparent in the supragranular layers of the cortex when control tissue (a), is compared with tissue from an individual with SZ (b). Size bar=400 μm.