Grant: CIHR Fellowship

Bipolar disorder (BD) is a severe psychiatric illness likely caused by the interaction between genetic and environmental factors, including a strong role for stress in disease manifestation. Genome-wide association studies have identified Ankyrin 3 (ANK3) as among the most statistically significant genes contributing to BD risk. The risk variant has also been linked to lower levels of ANK3 within the brain. Interestingly, mice with lower expression levels of Ank3 (Ank3+/- mice) show manic-like behavioural traits as well as elevated stress hormone (corticosterone). However, how ANK3 functions to alter stress sensitivity and if that altered sensitivity plays a role in BD risk is unknown. This research proposal seeks to evaluate the role of ANK3 in altered hypothalamic-pituitary-adrenal (HPA) axis stress reactivity associated with BD risk. We hypothesize that elevated corticosterone in Ank3+/- mice is due to HPA axis hyperactivation that heightens stress sensitivity. This will be tested by measuring HPA axis hormone levels and pharmacologically blocking specific points along the axis to attenuate the stress sensitivity of Ank3+/- mice to identify the specific brain region(s) within the HPA axis that function abnormally. The second aim of this proposal will translate the mouse data to human BD by determining if an association exists between human ANK3 genetic variation and HPA axis reactivity. We hypothesize that individuals carrying the ANK3 allele associated with BD risk will show elevated stress hormone levels (similarly to the Ank3+/- mice). These studies will begin to define the role of ANK3 in HPA axis stress reactivity and how this may contribute to BD risk. Given evidence indicating ANK3 is among the strongest genetic risk factors for BD and that chronic stress is a major environmental contributor to disease manifestation, investigating how they may interact will greatly aid our understanding of BD and our ability to develop effective treatments.