Grant: CIHR Fellowship

Bipolar disorder is a prevalent and devastating mental illness that is characterized by recurrent manic and depressive episodes. Medication is the cornerstone for treating bipolar disorder and includes mood stabilizers and antipsychotics. The development of new and improved treatments is greatly limited by our lack of understanding on how current treatments work. I will investigate the possibility that epigenetic factors may have an important role in the mechanisms of action of treatments for bipolar disorder. Epigenetics processes control gene activity without changing the DNA sequence. It acts as a "second code" of programming on top of the DNA code that, unlike DNA, can change over a lifetime. DNA methylation is an epigenetic mechanism that has been shown to be abnormal in bipolar patients, and treatments for this illness may ameliorate symptoms by causing changes in DNA methylation. To explore this possibility, mood stabilizers and antipsychotics will be administered to animal subjects, and changes in DNA methylation will be measured across the entire genome using a microarray technique. The microarray-based approach is unbiased and is a productive means of finding new genes affected by bipolar treatments via an epigenetic mechanism. The microarray findings will be confirmed with highly sensitive fine-mapping techniques. Epigenetic changes in response to drug treatments will be measured in both the normal mouse brain and in the brains of mutant mice that exhibit biochemical and behavioral disturbances resembling the symptoms of bipolar disorder. Nerve cells that originated from unmedicated human bipolar patients will also be exposed to bipolar medications and changes in DNA methylation will be measured. Overall, this study will provide insight on how treatments for bipolar disorder work and will reveal new gene targets involved in drug response. Identification of novel genes influenced by bipolar medications will fuel the development of improved treatments.