Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia

Abstract

Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n=41) and a comparison group (n=34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n=31) and unmedicated (n=10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia.

Figure 1

In situ hybridization using [³⁵S] labeled antisense riboprobes of a representative subject for motility-related protein-1 (CD9), Claudin-11 (CLDN11), gelsolin (GEL), myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), and peripheral myelin protein 22 (PMP22). Labeling for each is seen in the white matter (WM) and gray matter (GM) of the anterior cingulate cortex. The dashed line indicates the boundary of the white and gray matter, the solid line indicates the pial surface. Scale bar: 1mm

Figure 2

In situ hybridization using [³⁵S] labeled antisense riboprobes of a representative subject for 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP), erbb2 interacting protein (ErbB2IP), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ErbB3), oligodendrocyte transcription factor 2 (OLIG2), quaking (QKI), SRY-box containing gene 10 (SOX10), and transferrin (TF). Labeling for each is seen in the white matter (WM) and gray matter (GM) of the anterior cingulate cortex. The dashed line indicates the boundary of the white and gray matter, the solid line indicates the pial surface. Scale bar: 1mm

Figure 3

Motility-related protein-1 (CD9), Claudin-11 (CLDN11), gelsolin (GEL), myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), and peripheral myelin protein 22 (PMP22) transcript expression levels in the white matter (WM) and gray matter (GM) of the anterior cingulate cortex in schizophrenia and a comparison group. Decreased transcript expression was detected for MAG in the WM.

Figure 4

2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP), erbb2 interacting protein (ErbB2IP), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ErbB3), oligodendrocyte transcription factor 2 (OLIG2), quaking (QKI), SRY-box containing gene 10 (SOX10), and transferrin (TF) transcript expression levels in the white matter (WM) and gray matter (GM) of the anterior cingulate cortex in schizophrenia and a comparison group. Decreased transcript expression was detected for CNP, QKI, and TF in the WM.

Figure 5

2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP), transferrin (TF), quaking (QKI), and myelin-associated glycoprotein (MAG) transcript expression levels in white matter (WM) and gray matter (GM) of the anterior cingulate cortex in unmedicated (no antipsychotics within 6 weeks of death) and medicated subjects with schizophrenia.

Figure 6

Correlation analysis of quaking (QKI) and 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) or myelin-associated glycoprotein (MAG) transcript expression levels in the anterior cingulate cortex for all subjects studied (n =75). We found significant positive associations between QKI and CNP transcript expression and QKI and MAG transcript expression.