Grant: Operating Grant

Bipolar disorder (BD) is a major public health problem associated with significant functional impairment for many patients. The complete pathophysiology of this disorder remains under investigation, limiting the progress in the development of novel therapeutic strategies. There are, however, robust data supporting the increased activity of the dopaminergic system during mania, which is one of the key features of BD. In fact, antipsychotics have long been shown to exert their effects through the blockage of dopaminergic signalling, which has an important behavioral role in decreasing manic symptoms patients with BD. More recently, another interesting molecular pathway that has been consistently reported in BD is decreased mitochondrial function and increased oxidative stress, which can impair cell function. Interestingly, dopamine, its metabolites, and the proteins involved in the regulation of synaptic dopamine levels have been shown to be greatly vulnerable to oxidative stress. Although the relation between dopamine and oxidative stress has been shown to be critical in a number of neurological diseases, it has yet to be carefully examined in BD. Therefore, this proposal we will further investigate mitochondrial function and oxidative damage in brain tissue from patients with BD, focusing on the intracellular targets of oxidative stress at a subcellular level i.e. mitochondria, synapses, and study their relation to the dopaminergic system. We are particularly interested in how these changes can compromise neuronal function and thus be relevant to the manifestations of BD. Ultimately this project will allow us to identify potential biomarkers for BD and to elucidate more fully pathophysiological mechanisms that could lead to the development of novel therapeutic interventions for BD and consequently better patient care and outcomes.