Abstract
AbstractSuicide 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 thatNPAS4gene expression was downregulated whileALDH1A2, NAAA, andMLXIPLgene expressions were upregulated in tissue from suicide deaths. The gene ontology identified 29 significant pathways includingNPAS4-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 wereRELN, CRH, EMX2, OXTR, PARM1andIFITM2which overlapped with previously published results. The previously-known suicide-associated differentially expressed genes in differentiated neurons wereCOL1A1, THBS1, IFITM2, AQP1, andNLRP2. Together, these findings would help better understand the hippocampal neurobiology of suicide for identifying therapeutic targets to prevent suicide.
Publisher
Cold Spring Harbor Laboratory