THE TRANSCRIPTOMIC SIGNATURE OF THE PARAHIPPOCAMPAL CORTEX (PHC) ASSOCIATED WITH SUICIDE

Suicide constitutes a fatal outcome of neuropsychiatric conditions, associated with dysregulated network dynamics, markedly within the default mode network (DMN). The parahippocampal cortex (PHC), a functional interface between the DMN and the medial temporal lobe, supports affective regulation and contextual memory integration. PHC hyperactivity has been linked to suicidal mentation, and our previous proteomic findings indicated increased mitochondrial reliance on glutamine in PHC neurons. However, the transcriptomic architecture underlying suicidal behaviour remains insufficiently characterized.
We performed RNA sequencing on postmortem PHC tissue obtained from 11 suicide decedents and 11 matched controls. Differential expression was assessed with DESeq2, followed by functional annotation through Gene Ontology, Reactome pathway enrichment, and STRING protein–protein interaction network modelling. The key candidates were validated using qRT-PCR.
We identified 201 downregulated and 171 upregulated transcripts (|log2FC|>1, padj<0.05). Genes associated with axonal ensheathment exhibited prominent upregulation. Downregulated gene sets were linked to oxidative phosphorylation and G protein-coupled receptor (GPCR) signaling, whereas protein interaction networks further highlighted the suppression of chemokine-mediated neuroinflammatory pathways. The qRT-PCR confirmed a pronounced correlation with sequencing data (r=0.8712, p<0.0001) and validated increased expression of myelin sheath-related transcripts, including the ichthyin (NIPAL4), plakophilin-1 (PKP1) and the primarily oligodendroglial gliomedin (GLDN), alongside decreased expression of mitochondrial respiratory chain (MT-ATP6, MT-ND4) and neuronal GPCR signaling oxytocin receptor (OXTR) and adhesion G protein-coupled receptor G7 (ADGRG7) genes.
These findings define a PHC-specific molecular signature in suicide characterized by enhanced myelination, attenuated neuroimmune activity, and impaired mitochondrial ATP synthesis, offering novel insight into DMN vulnerability in suicide.