Animal Models of Schizophrenia
Genetics of Schizophrenia-Related Traits in Mice (PI: Hongxin Dong and John G. Csernansky, NIH grant pending) Schizophrenia is a common psychiatric disorder with a complex etiology involving genes, environment, and their interaction. Growing evidence indicates that abnormalities in brain structure and function demonstrate a key biological characteristic of schizophrenia. In this project, we are investigating the genetic basis of structural and functional alterations in thalamic-cortical circuitry using recombinant inbred (RI) mouse strains. We selected two BXD strains predicted to have either large or small thalamic and cortical volumes along with the appropriate genotype at marker D16Mit100 (a marker affecting both thalamic and cortical gray matter volumes). We then test behaviors related to working memory and executive function and their relationship to variation in thalamic-cortical neuroanatomical measurements. We then compare the cytoarchitectural features of thalamic-cortical circuitry in the BXD strains following behavioral testing. Finally, we measure patterns of gene expression in the thalamus and cortex in these two groups of BXD strains and determine whether these genes are located within the QTL of interest, or may interact with genes within the QTL of interest. This project will improve our understanding of the relationship between genetic influences and thalamic-cortical circuitry dysfunction in a powerful mouse model system, and shed light on the genetic basis of such dysfunction in individuals with schizophrenia.
Antipsychotic Therapy and Aging –Epigenetic Mechanisms (PI: Hongxin Dong and John G. Csernansky, NIH grant pending) Antipsychotic drugs are widely prescribed to elderly patients for the treatment of psychological disorders; however, the efficacy of antipsychotic medication treatment is questionable. Evaluation of the effects of antipsychotic therapy in the elderly is incomplete and the mechanisms of drug action are also not clearly addressed. One postulated mechanism of CNS aging asserts that genetic and epigenetic instability and alteration trigger a chain of events that eventually cause a decline in CNS function. Epigenetic alterations, such as global DNA hypomethylation, occur during aging. Other epigenetic processes, such as histone modification, also have defined roles in aging. Aberrant DNA methylation and histone acetylation have been linked to a number of age-related and psychiatric disorders. A growing number of studies have shown that antipsychotic drugs regulate histone remodeling and DNA demethylation. However, whether the epigenetic drift that transpires during aging suppresses the dynamic function and efficacy of antipsychotic drugs is not addressed. In this project, we will evaluate the interactions between epigenetic drift and antipsychotic regulation in the aged population by investigating the effects of selected antipsychotic drugs on aged mice using serial approaches from behavioral tests to DNA methylation and demethylation analysis. This study addresses important issues related to potential epigenetic changes during aging, and a novel mechanism of action for antipsychotic drugs on this population.