Induced pluripotent stem cell (iPSC) derived hippocampal dentate granule cell-like neurons from individuals with bipolar disorder (BD) are hyperexcitable and more spontaneously active relative to healthy control (HC) neurons. Furthermore, these abnormalities are normalised after the application of lithium in neurons derived from clinical lithium responders (LR) only. How these abnormalities impact hippocampal microcircuit computation is not understood. We aimed to investigate the impacts of BD-associated abnormal granule cell (GC) activity on pattern separation (PS) using a computational model of the dentate gyrus. We used parameter optimization to fit the parameters of biophysically realistic granule cell (GC) models to electrophysiological data from iPSC GCs from patients with BD. These cellular models were incorporated into dentate gyrus networks to assess impacts on PS using an adapted spatiotemporal task. Relationships between BD, lithium and spontaneous activity were analysed using a linear mixed-effects model. Lithium and BD negatively impacted PS, consistent with clinical reports of cognitive slowing and memory impairment during lithium therapy. By normalising spontaneous activity levels, lithium improved PS performance in LRs only. Improvements in PS after lithium therapy in LRs may therefore be attributable to the normalisation of spontaneous activity levels, rather than reductions in GC intrinsic excitability as we hypothesised. Our results mirror previous research demonstrating that mnemonic discrimination improves after lithium therapy in lithium responders only, supporting a hypothesised link between behavioural mnemonic discrimination and dentate gyrus PS. Our work can be expanded to also consider the effects of lithium-induced neurogenesis on PS.

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychology Neuroscience and Behaviour McMaster University Hamilton ON Canada

Faculty of Computer Science Dalhousie University Halifax NS Canada

Montreal Neurological Institute Department of Neurology and Neurosurgery McGill University Montréal QC Canada

National Institute of Mental Health Klecany Czech Republic

Sagol Department of Neurobiology Faculty of Natural Sciences University of Haifa Haifa Israel

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