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Biol Psychiatry. 2019 Oct 1. pii: S0006-3223(19)31743-3. doi: 10.1016/j.biopsych.2019.09.018. [Epub ahead of print]

Mechanisms Underlying the Hyperexcitability of CA3 and Dentate Gyrus Hippocampal Neurons Derived From Patients With Bipolar Disorder.

Author information

1
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel. Electronic address: sstern@univ.haifa.ac.il.
2
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California.
3
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
4
Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
5
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
6
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California; Laboratory of Dynamics of Neuronal Structure in Health and Disease, Institute of Psychiatry and Neuroscience of Paris (UMR_S1266 University of Paris), Paris, France.
7
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California. Electronic address: gage@salk.edu.

Abstract

BACKGROUND:

Approximately 1 in every 50 to 100 people is affected with bipolar disorder (BD), making this disease a major economic burden. The introduction of induced pluripotent stem cell methodology enabled better modeling of this disorder.

METHODS:

Having previously studied the phenotype of dentate gyrus granule neurons, we turned our attention to studying the phenotype of CA3 hippocampal pyramidal neurons of 6 patients with BD compared with 4 control individuals. We used patch clamp and quantitative polymerase chain reaction to measure electrophysiological features and RNA expression by specific channel genes.

RESULTS:

We found that BD CA3 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 dentate gyrus 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. Long-term 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 with 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.

KEYWORDS:

Bipolar disorder; Dentate gyrus; Hippocampus; Hyperexcitability; Motor neurons; Pyramidal

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