| The pathophysiology of bipolar disorder (BD) involves aberrant functioning at the molecular and cellular levels, including alterations in the BD biomarkers brain-derived neurotrophic factor (BDNF) and intracellular calcium homeostasis (ICH). However, disease- and cell-type relevant models for the examination of the disturbances in BD have been limited.;To this end, I sought to explore the validity and utility of the B Cell Lymphoblast Cell Line (BLCL) and Olfactory Neural Precursor (ONP) cell models in the study of BD pathophysiology, focusing on the pathophysiological significance of BDNF and ICH. BDNF protein expression was examined in BLCLs derived from lithium-responsive BD subjects, their unaffected relatives, and healthy controls (HC). In the neurally-relevant ONP cell lines, cell viability, cell proliferation, BDNF expression and basal intracellular calcium ([Cai2+]B) levels, as a marker of ICH, were determined.;This thesis work demonstrated lower BDNF levels in BLCLs derived from BD subjects compared to both their unaffected relatives and HC. BDNF levels in both treatment groups were also significantly decreased after cellular lithium treatment. After confirming that ONPs could be differentiated along a neural lineage, I then demonstrated that cell number is increased in ONPs in response to lithium treatment, and that ONPs derived from BD subjects have increased cell survival. Finally, in both treatment groups, BDNF protein and mRNA levels from ONPs decreased from 24 hour to 7 days, while lithium treatment resulted in a modest but significantly increased [Cai2+]B.;These results suggest an important role that lithium, due to its impact on cell proliferation, may have on neurogenesis. More importantly, increased ONP cell survival in BD supports a pathophysiological mechanism in BD, possibly affecting neurogenesis. Furthermore, the ONP model emerges as a disease- and cell type-relevant platform to examine the mechanistic and genetic basis underlying these abnormalities. These findings support the use of ONPs as a promising model for neuropsychiatric drug discovery. |
