Special Lecture Series with Michael McCarthy скачать в хорошем качестве

Special Lecture Series with Michael McCarthy

Title: Circadian rhythms in bipolar disorder patient-derived neurons and molecular mechanisms of lithium response Abstract: Bipolar disorder (BD) is defined by recurrent mood episodes, brain volume loss and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Interestingly, lithium affects the expression of “clock genes” the maintain circadian rhythms in cells, and lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. To examine circadian mechanisms underlying lithium response in more detail, we used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients clinically characterized for lithium response and matched controls. We identified strong circadian rhythms in Per2-luc expression in both NPCs and neurons. Compared to controls and Li-R, Li-NR rhythms were low-amplitude and profoundly weakened. Increased PER2 expression in BD neurons was observed and associated with weaker rhythms in Li-NR. In single cells, BD neurons show developmental differences in clock function. Moreover, BD rhythms were desynchronized compared to controls. In NPCs, PER1 protein in the cytoplasm and nucleus of NPCs was significantly higher in Li-NR compared to Li-R and controls and increases in PER1 expression were associated with apoptosis. PER1 knockdown led to more cell death in Li-NRs compared to Li-R and controls. During apoptosis, lithium reduced cytosolic PER1 only in the Li-NR cells and increased nuclear PER1 only in Li-R and controls. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR, and that there are distinct patterns of coordination between clock genes and apoptosis in Li-R and Li-NR with distinctive roles in regulating apoptosis in neuronal cells.