title: Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium.
abstract: Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Stern
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.|Ecole Normale Supérieure, PSL Research University, CNRS, Inserm, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Santos
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Marchetto
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: A P D
authors.initials: APD
authors.lastname: Mendes
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
authors.forename: G A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Biesmans
authors.affiliation: State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.
authors.forename: Q-W
authors.initials: QW
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.affiliation: Ecole Normale Supérieure, PSL Research University, CNRS, Inserm, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Charnay
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Bang
authors.affiliation: Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Alda
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: F H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000502:physiology*; D018891:Dentate Gyrus / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D008094:Lithium / Q000627:therapeutic use; D018020:Lithium Compounds / Q000627:therapeutic use; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques
chemical_list: D018692:Antimanic Agents; D014150:Antipsychotic Agents; D054316:Biomarkers, Pharmacological; D018020:Lithium Compounds; D008094:Lithium