2026 ECNP Congress

PS03-3098

Coupled bioenergetic and network dysfunction in hippocampal neurons associated with suicide in bipolar disorder

Yara Hussein — N. Halabi, A. Squassina, M. Alda, S. Stern · University of Haifa, Sagol Department of nuerobiology, Haifa, Israel

2026 ECNP Congress

Background:Bipolar disorder (BD) 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 BD have an approximately 20–30-fold higher suicide mortality rate than the general population, accounting for ~3–14% of all suicide deaths [1–3]. Despite this substantial clinical burden, the biological mechanisms underlying suicide vulnerability remain incompletely understood, limiting the development of predictive biomarkers and targeted interventions. Converging evidence implicates both mitochondrial dysfunction and altered neuronal network dynamics in BD pathophysiology; however, their contribution to suicide risk at the cellular level remains unclear. Human-induced pluripotent stem cell (iPSC)-derived neuronal models provide a powerful platform for investigating patient-specific molecular and functional phenotypes in disease-relevant cell types. In particular, hippocampal dentate gyrus (DG) neurons are of interest given their central role in stress responsivity, mood regulation, and neuroplasticity, processes that are disrupted in BD and implicated in suicidal behavior. Methods:Peripheral blood mononuclear cells (PBMCs) from BD patients who died by suicide and BD patients without a history of suicide completion, along with healthy controls, were immortalized using Epstein–Barr virus and reprogrammed via non-integrating episomal vectors into iPSCs. These iPSCs were differentiated into hippocampal DG-like neurons using established protocols. Mitochondrial function was assessed using Seahorse extracellular flux analysis, measuring oxygen consumption rate (OCR) as an indicator of oxidative phosphorylation and extracellular acidification rate (ECAR) as a proxy for glycolytic activity. Neuronal network activity was evaluated using calcium imaging to quantify spontaneous activity, firing dynamics, synchrony, and network organization across neuronal populations. Results:Dentate gyrus-like neurons derived from BD patients exhibited significant mitochondrial dysfunction compared to controls, reflected by altered OCR and ECAR profiles, indicating disrupted cellular bioenergetics. These abnormalities were more pronounced in neurons derived from suicide completers relative to non-suicide BD patients, suggesting a gradient of impairment associated with suicide outcome. Calcium imaging analyses revealed increased overall neuronal activity in BD-derived neurons, particularly in the suicide group. Notably, this hyperactivity was accompanied by reduced synchrony and impaired coordination across neuronal networks, indicating a shift toward a hyperactive yet disorganized network state. Together, these findings suggest that mitochondrial dysfunction is closely associated with altered neuronal excitability and network instability. Conclusions:Our findings demonstrate that hippocampal DG neurons derived from BD patients exhibit convergent mitochondrial and network-level dysfunction, with more severe impairments in individuals who were stratified by suicide outcome. The combination of altered bioenergetics (OCR/ECAR imbalance) and dysregulated neuronal network behavior, increased activity coupled with reduced synchrony, may represent a cellular signature of suicide vulnerability in BD. These results highlight the importance of integrating metabolic and functional phenotyping in iPSC-based models to better understand disease mechanisms. Such approaches may facilitate the identification of novel biomarkers and therapeutic targets aimed at reducing suicide risk in bipolar disorder.

References

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