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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)139-149
Number of pages11
JournalBiological Psychiatry
Volume88
Issue number2
DOIs
StatePublished - 15 Jul 2020

Bibliographical note

Funding Information:
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 samples and the clinical data were obtained with support from Canadian Institutes of Health Research Grant No. 64410 (to MA and GR). We thank Mary Lynn Gage for editing the article. We thank the Salk core facilities, and in addition, we thank the Engamm Foundation, JPB Foundation, and Streim Foundation. The authors report no biomedical financial interests or potential conflicts of interest.

Funding Information:
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 samples and the clinical data were obtained with support from Canadian Institutes of Health Research Grant No. 64410 (to MA and GR). We thank Mary Lynn Gage for editing the article. We thank the Salk core facilities, and in addition, we thank the Engamm Foundation, JPB Foundation, and Streim Foundation. The authors report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2019 Society of Biological Psychiatry

Keywords

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

ASJC Scopus subject areas

  • Biological Psychiatry

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