Scientific Report 2006

Molecular Biology

Molecular Neurobiology of CNS Disorders

E.A. Thomas, J.G. Sutcliffe, P.A. Desplats, S. Narayan, K.E. Kass, T. Gilmartin, L. Schaffer, S.R. Head

Gene Profiling in Schizophrenia

Schizophrenia is a life-long, heterogeneous mental illness with variable expression and unknown etiology. We are interested in the molecular factors that influence the course of illness in schizophrenia and how treatment modifies these factors. Using oligonucleotide microarrays, we generated gene expression profiles from tissue samples obtained at autopsy from the prefrontal cortex of patients with schizophrenia of short, intermediate, and long duration and from the prefrontal cortex of matched control subjects without schizophrenia. Among many genes and pathways revealed as significantly altered in schizophrenia, we are focusing on those related to glycosphingolipid metabolism and myelination. A total of 40 genes with altered expression in patients with schizophrenia were related to these systems.

To assess the effects of treatment with antipsychotic drugs on a subset of genes that encode structural components of myelin, we treated groups of mice with haloperidol, a widely prescribed “typical” antipsychotic drug. Chronic haloperidol treatment caused significant decreases in the expression levels of at least 8 myelin-related genes in several white matter regions of mouse brain as revealed by in situ hybridization analysis.

In other studies, we are investigating the molecular basis for heterogeneity in schizophrenia by identifying genes that have similar expression profiles in subsets of patients with the disorder. Using weighted gene coexpression network analyses, we identified distinct subtypes in our schizophrenia cohort, most notably, dramatic differences in the expression profiles between patients with short versus long duration of illness. We are exploring subtype-specific pathways associated with these subgroups.

Transcriptional Dysregulation in Huntington’s Disease: Striatal Specificity

Much evidence supports a role for transcriptional dysregulation in Huntington’s disease. Of particular interest is how these disturbances may be specifically manifested in the striatum, the primary region of neurodegeneration in Huntington’s disease. Using microarray analysis and a transgenic mouse of Huntington’s disease, we identified a cluster of striatal-enriched genes that was downregulated in the mice. The cluster included the genes FoxP1, Bcl11b, and DRRF, which encode zinc finger–containing transcription factors, and RARB and RXRG, which encode nuclear receptors. Real-time polymerase chain reaction validated 57% and 40% reductions in levels of Bcl11b and FoxP1 mRNA, respectively, in the striatum of symptomatic transgenic mice and a 73% decrease in the expression of FoxP1 in human caudate from patients with Huntington’s disease. Transcripts for both of these factors are expressed in medium spiny projection neurons, which selectively degenerate in Huntington’s disease. Further colocalization and coimmunoprecipitation studies have suggested that Bcl11b and FoxP1 interact with polyglutamine-expanded N-terminal huntingtin. Sequestration of these factors into nuclear aggregates in Huntington’s disease resulting in loss of function may contribute to specific dysregulation of striatal gene expression. This mechanism may explain, in part, the specificity of the pathologic changes associated with Huntington’s disease.

Publications

Desplats, P.A., Kass, K.E., Gilmartin, T., Stanwood, G.D., Woodward, E.L., Head, S.R., Sutcliffe, J.G. Thomas. E.A. Selective deficits in the expression of striatal-enriched mRNAs in Huntington’s disease. J. Neurochem. 96:743, 2006.

Thomas, E.A. Apolipoprotein D and arachidonic acid interactions in the treatment and pathology of schizophrenia. In: Fatty Acids and Oxidative Stress in Neuropsychiatric Disorders. Yao, J.K. (Ed.). Nova Science Publishers, Inc., Hauppauge, NY, 2006.

Narayan, S., Kass, K.E., Thomas, E.A. Chronic haloperidol treatment results in a decrease in the expression of myelin/oligodendrocyte-related genes in the mouse brain. J. Neurosci. Res., in press.

Thomas, E.A., Yao, J.K. Clozapine specifically alters the arachidonic acid pathway in mice lacking apolipoprotein D. Schizophr. Res., in press.

Thomas, E.A. Molecular profiling of antipsychotic drug function: convergent mechanisms. In: The Pathology and Treatment of Psychiatric Disorders. Molecular Neurobiology, in press.

Thomas, E.A. Striatal specificity of gene expression dysregulation in Huntington's disease. J. Neurosci. Res. 84:1151, 2006.