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