Suicide is a condition resulting from complex environmental and genetic risks that affect millions of people globally. Both structural and functional studies identified the hippocampus as one of the vulnerable brain regions contributing to suicide risk. Here, we have identified the hippocampal transcriptomes, gene ontology, cell type proportions, dendritic spine morphology, and transcriptomic signature in iPSC-derived neuronal precursor cells (NPCs) and neurons in postmortem brain tissue from suicide deaths. The hippocampal tissue transcriptomic data revealed that NPAS4 gene expression was downregulated while ALDH1A2, NAAA, and MLXIPL gene expressions were upregulated in tissue from suicide deaths. The gene ontology identified 29 significant pathways including NPAS4-associated gene ontology terms 'excitatory post-synaptic potential', 'regulation of postsynaptic membrane potential' and 'long-term memory' indicating alteration of glutamatergic synapses in the hippocampus of suicide deaths. The cell type deconvolution identified decreased excitatory neuron proportion and an increased inhibitory neuron proportion providing evidence of excitation/inhibition imbalance in the hippocampus of suicide deaths. In addition, suicide deaths had increased dendric spine density, due to an increase of thin (relatively unstable) dendritic spines, compared to controls. The transcriptomes of iPSC-derived hippocampal-like NPCs and neurons revealed 31 and 33 differentially expressed genes in NPC and neurons, respectively, of suicide deaths. The suicide-associated differentially expressed genes in NPCs were RELN, CRH, EMX2, OXTR, PARM1 and IFITM2 which overlapped with previously published results. The previously-known suicide-associated differentially expressed genes in differentiated neurons were COL1A1, THBS1, IFITM2, AQP1, and NLRP2. Together, these findings would help better understand the hippocampal neurobiology of suicide for identifying therapeutic targets to prevent suicide.

The authors have declared no competing interest.

National Institute of Mental Health [R01MH122412 and R01MH123489 to HC] [R01MH085801 to MPV]; American Foundation for Suicide Prevention (AFSP) [to SCD, 2019 Pilot Research Grant (AFSP Grant ID# PRG-1-032-18)]; University of California Della Martin Foundation [to SCD, Postdoctoral Fellowship]. Postmortem brain collection at the University of California-Irvine (UCI) Brain Bank was supported by the Pritzker Neuropsychiatric Disorders Research Consortium.

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The brain and skin biopsy sample collection at the University of Utah were approved under an exemption (45CFR46.102(f)) from the Institutional Review Board (IRB). The postmortem brain collection at the UCI was also approved by the UCI Institutional Review Board (IRB).

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