Use of patient-derived cellular models to investigate the mechanistic basis of circadian dysfunctions and chronomodulatory drugs in bipolar disorder

Bipolar disorder is a highly incapacitating neuropsychiatric disorder, where patients exhibit cycling episodes of mania and depression. In addition to these characteristics, sleep and circadian rhythm disruptions are frequently observed through changes in physiology and behaviour. Lithium treatment remains effective in inducing acute and long-term mood stabilisation, yet there is ambiguity as to how it exerts its therapeutic benefits. As lithium induces significant chronomodulatory effects, one possible mechanism may be via the alteration of circadian rhythms. Using virally transduced bipolar patient-derived fibroblasts, we investigated basal circadian rhythms, as well as the cellular responses to chronomodulatory agents in order to identify any aberrancies. We then went on to investigate the mechanism via which lithium induces its chronomodulatory effects. The use of patient-derived fibroblasts revealed the presence of circadian abnormalities, manifesting as a broad distribution of period lengths. Further, patients with a longer period phenotype exhibited muted chronomodulatory changes following lithium treatment. These changes were not restricted to lithium and were also observed with two novel chronomodulators. Remarkably, these compounds also exhibited changes to circadian rhythms and displayed lithium-like behaviours in vivo, highlighting their translational potential. We subsequently went on to confirm that lithium inhibited two major receptor coupled systems: inositol monophosphatase and adenylate cyclase. Using immortalised cell lines, we showed that lithium induces period lengthening predominantly via perturbing the phosphoinositide pathway, which elevates expression of the transcription factor C/EBPα. Whilst we found that adenylate cyclase signalling plays a contributory but subordinate role in mediating period effects, such information may be vital in informing future drug discovery processes, as it could enable the identification of mechanistically novel mood- stabilisers with fewer undesirable side effects. Thus, in this DPhil thesis, we present data highlighting that patient-derived fibroblasts could be instrumental tools which could perpetuate the drug discovery process, and suggest that C/EBPα may be responsible for lithium-induced circadian period lengthening.