Elsevier

Biological Psychiatry

Volume 88, Issue 2, 15 July 2020, Pages 139-149
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2019.09.018Get rights and content

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.

Section snippets

Patients

The cohort in this study consisted of the same patients used in the previous study (14). Supplemental Table S1 summarizes their clinical data. The cohort consisted of 4 control individuals, 3 patients with LR BD, and 3 patients with NR BD. All experiments were performed on all 10 lines (Supplement).

DG Neurons

Using iPSC technology, DG granule neurons were cultured according to our published protocol (19) and measured at 4.5 weeks (time 2 [t2]) and 2.5 weeks (t1) (Supplement).

CA3 Neurons

Using iPSC technology, CA3

CA3 Pyramidal Neurons Derived From Patients With BD Are Hyperexcitable Only When Derived From LR Patients, and Spike Shape Properties Are Altered

Both DG and CA3 neurons were patch clamped at time point t2 (4.5 weeks). We partitioned our data into 3 groups: neurons derived from control individuals, neurons derived from patients with BD who responded to lithium (LR), and neurons derived from patients with BD who did not respond to lithium (NR). Around 60% of the neurons in the 3 groups were CA3 pyramidal neurons, expressing ELAVL2 (a specific CA3 protein) (see Supplemental Figure S1A, C for immunostaining), and approximately 12% of the

Discussion

BD affects approximately 1.5% to 2% of the worldwide population, putting a huge burden on the world’s health and economic systems. Animal models do not fully recapitulate this disorder, either phenotypically or genetically. The introduction of iPSC technology has allowed us for the first time to study this disorder in a dynamic human model and enabled us to define an endophenotype of this disorder in the form of DG overexcitability (13,14). Having developed a new protocol for CA3 pyramidal

Acknowledgments and Disclosures

This work was supported in part by the National Cancer Institute (Grant No. P30 CA014195) and the National Institutes of Health (Grant No. R01 AG05651 [to FG]) and by the National Cooperative Reprogrammed Cell Research Groups (NCRCRG) (Grant No. U19 MH106434 [to FG]). The Gage laboratory is supported in part by the Leona M. and Harry B. Helmsley Charitable Trust Grant No. 2017-PG-MED001, the JPB Foundation, Annette C. Merle-Smith, and the Robert and Mary Jane Engman Foundation. The lymphoblast

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