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

Shani Stern, Anindita Sarkar, Dekel Galor, Tchelet Stern, Arianna Mei, Yam Stern, Ana P D Mendes, Lynne Randolph-Moore, Guy Rouleau, Anne G Bang, Renata Santos, Martin Alda, Maria C Marchetto, Fred H Gage

Journal: Biological psychiatry 2021;88(2):150-158

PMID: 32278494

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Abstract

BACKGROUND

We recently reported a hyperexcitability phenotype displayed in dentate gyrus granule neurons derived from patients with bipolar disorder (BD) as well as a hyperexcitability that appeared only in CA3 pyramidal hippocampal neurons that were derived from patients with BD who responded to lithium treatment (lithium responders) and not in CA3 pyramidal hippocampal neurons that were derived from patients with BD who did not respond to lithium (nonresponders).

METHODS

Here we used our measurements of currents in neurons derived from 4 control subjects, 3 patients with BD who were lithium responders, and 3 patients with BD who were nonresponders. We changed the conductances of simulated dentate gyrus and CA3 hippocampal neurons according to our measurements to derive a numerical simulation for BD neurons.

RESULTS

The computationally simulated BD dentate gyrus neurons had a hyperexcitability phenotype similar to the experimental results. Only the simulated BD CA3 neurons derived from lithium responder patients were hyperexcitable. Interestingly, our computational model captured a physiological instability intrinsic to hippocampal neurons that were derived from nonresponder patients that we also observed when re-examining our experimental results. This instability was caused by a drastic reduction in the sodium current, accompanied by an increase in the amplitude of several potassium currents. These baseline alterations caused nonresponder 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 patients with BD.

Address: Laboratory of Genetics, Gage Lab, Salk Institute for Biological Studies, La Jolla, California; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel. Electronic address: [email protected].; Laboratory of Genetics, Gage Lab, Salk Institute for Biological Studies, La Jolla, California.; Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.; Laboratory of Genetics, Gage Lab, Salk Institute for Biological Studies, La Jolla, California; University of Paris, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Laboratory of Dynamics of Neuronal Structure in Health and Disease, Paris, France.; Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.; Laboratory of Genetics, Gage Lab, Salk Institute for Biological Studies, La Jolla, California. Electronic address: [email protected].

DOI: 10.1016/j.biopsych.2020.01.020

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MeSH Terms: Bipolar Disorder, Dentate Gyrus, Hippocampus, Humans, Lithium, Neurons, Pyramidal Cells