Mechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from bipolar disorder patients.

Abstract Background Approximately one in every 50-100 people is affected with bipolar disorder (BD), making this disease a major economic burden. The introduction of the induced pluripotent stem cells (iPSCs) methodology enabled better modeling of this disorder. Methods Having previously studied the phenotype of dentate gyrus (DG) granule neurons, we turned our attention to studying the phenotype of CA3 hippocampal pyramidal neurons of 6 BD patients compared to 4 control individuals. We used patch clamp and qPCR to measure electrophysiological features and RNA expression by specific channel genes. Results We found that CA3 BD neurons were hyperexcitable only when they were derived from patients who responded to lithium; they featured sustained activity with large current injections and a large, fast after-hyperpolarization, similar to what we previously reported in DG neurons. The higher amplitudes and faster kinetics of fast potassium currents correlated with this hyperexcitability. Further supporting the involvement of potassium currents, we observed an overexpression of Kcnc1 and Kcnc2 in hippocampal neurons derived from lithium responders. Applying specific potassium channel blockers diminished the hyperexcitability. Chronic lithium treatment decreased the hyperexcitability observed in the CA3 neurons derived from lithium responders, while increasing sodium currents and reducing fast potassium currents. When differentiating this cohort into spinal motor neurons, we did not observe any changes in the excitability of BD motor neurons compared to control motor neurons. Conclusions The hyperexcitability of BD neurons is neuronal type specific with the involvement of altered potassium currents that allow for a sustained, continued firing activity.