A Physiological Instability Displayed in Hippocampal Neurons Derived From Lithium-Nonresponsive Bipolar Disorder Patients

Abstract

Background: We recently reported a hyperexcitability phenotype displayed in dentate gyrus (DG) granule neurons derived from bipolar disorder (BD) patients (1, 2) and also a hyperexcitability that appeared only in CA3 pyramidal hippocampal neurons that were derived from BD patients who responded to lithium treatment (LR) but not from BD patients who were lithium non-responders (NR) (3). Methods: Here we used our measurements of currents in neurons derived from 4 control individuals, 3 LR BD patients, and 3 NR BD patients. We have changed the conductances of simulated DG and CA3 hippocampal neurons according our measurements to derive a numerical simulation for BD neurons. Results: The computationally simulated BD DG neurons had a hyperexcitability phenotype similar to the experimental results. The simulated BD CA3 neurons were only hyperexcitable when derived from LR BD patients. Interestingly, our computational model captured a physiological instability intrinsic to hippocampal neurons that were derived from NR BD patients that we also observed when reexamining our experimental results. This instability is caused by a drastic reduction in the sodium current, accompanied by an increase in the amplitude of the fast potassium currents. These baseline alterations cause NR BD hippocampal neurons to drastically shift their excitability with small changes to their sodium currents, alternating between hyperexcitable and hypoexcitable states. Conclusions: Our computational model of BD hippocampal neurons that was based on our measurements reproduced the experimental phenotypes of hyperexcitability and physiological instability. We hypothesize that the physiological instability phenotype strongly contributes to affective lability in BD patients.

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“…This instability was caused by a reduction in the sodium current and increased potassium current amplitude. The computational model further confirmed the role of increased potassium currents in BD hippocampal neuronal hyperexcitability [130]. Recently, Mishra et al (2021) studied lithium effects on circadian rhythms in BD patients' neurons.…”

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“…Mertens and colleagues (5) demonstrated hyperactivity in iPSC-derived dentate gyrus neurons derived from patients, which was reversed by lithium only in those derived from patients who were lithium responsive. In follow-up studies, the same group replicated these findings, successfully predicted the lithium responsiveness of a patient using a classifier trained on electrophysiological parameters of the responder vs. non-responder cells (41), and suggested that hippocampal CA3 hyperexcitability might be unique to lithium responders (42), and reduced by lithium exposure (43). However, the studies conducted to date have been used small samples and have emerged from a single laboratory.…”

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“…Mertens and colleagues (5) demonstrated hyperactivity in iPSC-derived dentate gyrus neurons derived from patients, which was reversed by lithium only in those derived from lithium-responsive patients. In follow-up studies, the same group replicated these findings, successfully predicted the lithium responsiveness of a patient using a classifier trained on electrophysiological parameters of responder vs. non-responder cells (38), and suggested that hippocampal CA3 hyperexcitability might be unique to lithium responders (39), and reduced by lithium exposure (40). However, these studies used small samples and emerged from a single laboratory.…”