1. ¹Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA
2. ²JJ Peters VA Medical Center, Bronx, NY, USA

Correspondence: Dr P Katsel, Department of Psychiatry, Room 4F-20, JJ Peters VA Medical Center, Research Build. (151), 130 West Kingsbridge Road, Bronx, NY 10468, USA. Tel: +1 718 584 9000 ext 6067; Fax: +1 718 365 9622; E-mail: pavel.katsel@mssm.edu

Received 13 November 2007; Revised 23 January 2008; Accepted 24 January 2008; Published online 5 March 2008.

Abstract

The goal of this study was to determine what signaling pathways may elicit myelin-specific gene expression deficits in schizophrenia (SZ). Microarray analyses indicated that genes associated with canonical cell cycle pathways were significantly affected in the anterior cingulate gyrus (ACG), the region exhibiting the most profound myelin-specific gene expression changes, in persons with SZ (N=16) as compared with controls (N=19). Detected gene expression changes of key regulators of G1/S phase transition and genes central to oligodendrocyte differentiation were validated using qPCR in the ACG in an independent cohort (Ns=45/34). The relative abundance of phosphorylated retinoblastoma protein (pRb) was increased in the white matter underlying the ACG in SZ subjects (Ns=12). The upregulation of cyclin D1 gene expression and the downregulation of p57^Kip2, accompanied by increased cyclin D/CDK4-dependent phosphorylation of pRb, acting as a checkpoint for G1/S phase transition, suggest abnormal cell cycle re-entry in postmitotic oligodendrocytes in SZ. Furthermore, gene expression profiling of brain samples from myelin mutant animal models, quaking and myelin-associated glycoprotein (MAG) null mice, showed that cell cycle gene expression changes were not a necessary consequence of the reduced gene expression of structural myelin proteins, such as MAG. While, quaking, a known modulator of cell cycle activity during oligodendrocyte differentiation impairs the expression of multiple myelin genes, including those that are affected in SZ. These data suggest that the normal patterns of cell cycle gene and protein expression are disrupted in SZ and that this disruption may contribute to the oligodendroglial deficits observed in SZ.