Background:
Schizophrenia is a major psychiatric disorder that affects approximately 1% of people during their lifetimes. Antipsychotic drugs are the most effective treatment for the psychotic phase of schizophrenia, although their mechanism of action remains largely unknown.
Methods:
We have treated mice with one of three antipsychotics to create animal models of antipsychotic drug action. Control mice were treated with saline. Drug treatment was performed by means of daily intra-peritoneal injections for 1 and 4 weeks. RNA was extracted from the brains of these mice and hybridized to whole-genome microarray chips. Validation of mRNA expression changes in selected genes was undertaken using quantitative polymerase chain reaction (PCR) and protein expression was investigated using Western blot analysis.
Results:
Data analysis showed that many genes were dysregulated by antipsychotic drug treatment, including those involved in signal transduction, synaptic transmission and neurogenesis. Genes were selected for further analysis based upon their coregulation by different antipsychotics, chromosomal location or known molecular function. Changes in gene expression were confirmed for 13 of 19 genes thus far analyzed by quantitative PCR. Western blot analysis indicated that these changes in mRNA levels are translated into protein expression changes in at least two genes; neural precursor cell developmentally downregulated gene 4 (Nedd4) and potassium voltage-gated channel, shaker-related subfamily, member 1 (Kcnal ).
Conclusions:
This study has shown that Nedd4 and Kcnal, genes encoding proteins either forming ion channels or modulating their activity, showed dysregu-lation following treatment with antipsychotics, which may provide important clues to the pathogenesis of schizophrenia.
