Grant: Operating Grant

Bipolar disorder (BD) is characterized by severe mood episodes, high comorbidity, and functional deterioration, carrying a suicide rate of approximately 15%. Several molecular pathways have been identified in the disease processes in BD. Neurotrophic factors, implicated in BD, are growth factors important in these pathways and in survival of brain tissue. Specifically, Brain Derived Neurotrophic Factor (BDNF) is decreased in B lymphoblast cell lines (BLCLs) and serum of manic and depressed BD patients, and increases with antidepressant and mood stabilizer treatment, as observed in human post-mortem hippocampus and serum studies of depressed subjects. BDNF action has been linked to specific cell membrane calcium channels, the type 3 and type 6 canonical Transient Receptor Potential (TRPC) channels, which regulate calcium entry into cells thereby generating calcium signalling in the cell. BDNF-TRPC3/6 activation has been implicated in cellular survival, and recently enhanced TRPC3-like activity has been observed in BLCLs from patients with BD. The study of peripheral models such as BLCLs is advantageous given the difficulty in accessing live human brain tissue. The general objective of this research proposal is to test whether the BDNF/TRPC3 association established in other cell lines holds true in BLCLs, and secondly, to determine how this BDNF-TRPC3 interaction is impaired in BD subjects and involved in the mechanism of action of mood stabilizing medications. We will also extend our findings into human neuronal models, to give a closer approximation of what happens in neurons in the brain. Examining the relationship between BDNF and TRPC3 in BLCLs from BD subjects, and extending these findings into neuronal models, will allow for a better understanding of the disease process of BD in these reporter models, and provide a stronger link between cellular models and the brain. This will also guide new medication discovery for bipolar disorder.