Using advanced single-nucleus RNA sequencing and chromatin accessibility assays, researchers mapped over two million nuclei from human prefrontal cortex samples from PTSD patients, depressed patients, and controls. They identified marked reductions in signaling from somatostatin-expressing interneurons (SST INs), essential for inhibitory neurotransmission, in PTSD brains. This loss correlates with disrupted neurotransmitter pathways and impaired synaptic regulation, illuminating molecular and cellular mechanisms underlying PTSD’s neuropsychiatric manifestations. The study highlights altered gene expression profiles and receptor activity in key neuronal and glial populations, offering targets for therapeutic intervention in PTSD and major depressive disorder.