A groundbreaking new study delves into the intricate cellular communication disruptions underlying post-traumatic stress disorder (PTSD), revealing pivotal changes in brain cell signaling that may redefine how we understand this debilitating condition. Using advanced single-cell transcriptomic analyses, researchers have pinpointed specific alterations in how neurons and glial cells communicate, highlighting the diminished role of somatostatin-expressing interneurons (SST INs) and their synaptic interactions in the prefrontal cortex of individuals with PTSD.
At the heart of this discovery lies a comprehensive cell–cell communication (CCC) network constructed from ligand–receptor pairs derived from transcript expression data. This network allowed scientists to trace the intricate dialogues between different brain cell types. Strikingly, the study found a pronounced reduction in signaling emanating from SST interneurons in PTSD samples compared to controls. These interneurons, known for modulating neuronal excitability and maintaining inhibitory tone, exhibited significant decreases in their capacity to send neurotransmitter signals, suggesting a critical impairment in inhibitory control within the cortical circuitry.
The diminished communication from SST interneurons impacts a wide array of neuronal targets, particularly other inhibitory neurons such as KCNG1-expressing subtypes, and extends to astrocytes, endothelial cells, and oligodendrocyte precursor cells. This broad decline in signaling indicates that the disruption is not limited to a single cell type but affects the larger cellular ecosystem of the brain, potentially contributing to the complex symptomatology of PTSD.
One of the most revealing aspects of the study is the downregulation of the somatostatin (SST) gene itself across interneurons in the dorsolateral prefrontal cortex (DLPFC), a critical hub for executive function and emotional regulation. This transcriptional decline correlates with reduced expression of key GABA transporters, notably SLC32A1, which is essential for the packaging and release of the inhibitory neurotransmitter GABA. The near absence of this transporter in the PTSD group underscores a fundamental breakdown in inhibitory neurotransmission.
Further molecular investigations demonstrated that the decreased GABA output from SST interneurons leads to diminished activation of specific GABA receptor subunits, including GABRA5, GABBR1, GABRB1, and GABRG1, on post-synaptic neurons. These receptors mediate various inhibitory responses that are fundamental to controlling neuronal excitability and maintaining the delicate balance between excitation and inhibition in cortical networks. The disruption of this balance is a plausible mechanistic explanation for the heightened neural activity and emotional dysregulation seen in PTSD.
To corroborate these transcriptomic findings, the research team employed a rodent model of traumatic stress known as single prolonged stress (SPS). In this model, electrophysiological recordings using optogenetics revealed a marked reduction in inhibitory postsynaptic currents (IPSCs) mediated by SST interneurons onto pyramidal excitatory neurons. Application of a selective GABRA5 antagonist, MRK 016, further confirmed the critical role of this receptor subtype in SST-to-excitatory neuron synaptic transmission. In stressed animals, the antagonist produced a significantly attenuated effect, mirroring the diminished synaptic efficiency observed in humans with PTSD.
Complementing synaptic deficits, the study also evaluated tonic inhibition mediated by GABA_B receptors, which modulate neuronal activity over longer timescales. Blocking these receptors with CGP 55845 resulted in substantially smaller decreases in tonic inhibitory currents in SPS animals compared to controls, indicating impaired GABA_B receptor function and suggesting widespread inhibitory deficits beyond conventional synaptic transmission.
Beyond the GABAergic system, the investigation uncovered dysregulation in multiple neurotransmitter-receptor interactions involving glutamate and neuropeptides such as corticotropin-releasing hormone (CRH) and cortistatin (CORT). Notably, pathways such as Glu-GRM2 and CORT-SSTR2 exhibited reduced signaling in PTSD, while CRH-CRHR1 communication was paradoxically heightened, reflecting hyperactivation of stress-related neuroendocrine circuits. This nuanced picture points to a complex rewiring of excitatory and inhibitory networks in the PTSD brain.
Delving deeper, cell-type-specific analyses revealed that CRH signaling is predominantly increased from vasoactive intestinal peptide (VIP) interneurons to CUX2-expressing excitatory neurons, implying an augmented stress response within distinct microcircuits. Similarly, altered glutamatergic signaling between specific excitatory neuron subtypes and oligodendrocyte precursor cells suggests potential disruptions in myelination and neuronal support systems in PTSD.
The study also implicated microglial cells in the altered communication landscape of PTSD, noting decreased microglial sending patterns mediated by the upregulation of the SPP1 gene encoding osteopontin. Osteopontin receptors, especially integrin α4 subunits on neurons, exhibited differential regulation in PTSD versus major depressive disorder (MDD), hinting at divergent immune-neuronal interactions across psychiatric disorders.
Collectively, these findings signal a paradigm shift in PTSD research, moving from broad systemic perspectives to a refined understanding of synaptic, cellular, and molecular dysfunctions. The convergence of transcriptomic alterations and functional deficits at the inhibitory synapse, especially involving SST interneurons and GABA receptor subtypes, provides compelling targets for therapeutic intervention. Modulating these signaling pathways could restore inhibitory balance and ameliorate PTSD symptoms.
With this comprehensive cellular and molecular map of PTSD cortex communications, the research lays the groundwork for precision medicine strategies aimed at correcting specific neurotransmission deficits. Future studies leveraging such single-cell and circuit-level insights may revolutionize the diagnosis and treatment landscape for trauma-related disorders, offering hope to millions affected worldwide.
Subject of Research: Single-cell transcriptomic and chromatin dynamics of the human brain in post-traumatic stress disorder (PTSD).
Article Title: Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD.
Article References:
Hwang, A., Skarica, M., Xu, S. et al. Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD. Nature (2025). https://doi.org/10.1038/s41586-025-09083-y
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