HIPPOCAMPAL DG HYPEREXCITABILITY IN IPSC-DERIVED NEURONS FROM BD PATIENTS STRATIFIED BY SUICIDE OUTCOME

Background: Bipolar disorder carries one of the highest suicide risks among psychiatric illnesses, with 25-50% of patients attempting suicide and 8-19% dying by suicide.
Individuals with bipolar disorder have a 10-30-fold higher suicide mortality rate than the general population, accounting for approximately 3-14% of all suicide deaths.
Methods: Peripheral blood from bipolar disorder patients who either died by suicide or had no history of suicide completion was immortalized with EBV, reprogrammed using non-integrating episomal vectors, and differentiated into hippocampal dentate gyrus (DG) like neurons.
Whole-cell patch clamp recordings quantified spontaneous excitatory postsynaptic currents (sEPSCs), sodium and fast/slow potassium currents, current-evoked action potentials (APs), and spontaneous AP firing.
Results: Across the bipolar cohort, DG-neurons exhibited a hyperexcitable phenotype, with significantly more evoked APs (P < 0.01), higher sEPSC frequency (P < 0.01), and greater sEPSC amplitude (P < 0.05) than control values under the recording conditions. Within-patient comparisons revealed that neurons from suicide completers showed a more extreme hyperexcitable profile than neurons from non-suicide patients, with greater evoked AP firing (P < 0.01), higher sEPSC rates (P < 0.01), and increased sEPSC amplitudes (P < 0.05).
Conclusions: These data indicate that hippocampal DG neurons derived from BD patients are intrinsically hyperexcitable, with further amplification of this phenotype in individuals who died by suicide. The findings support neuronal hyperexcitability as a potential cellular correlate of suicide vulnerability in BD and suggest that iPSC-based electrophysiology may help identify mechanistic and therapeutic targets for suicide prevention.