Altered glutamatergic neurotransmission in the development and maintenance of PTSD

Post-traumatic stress disorder (PTSD) is a multifactorial neuropsychiatric condition characterized by persistent disturbances in fear processing, emotional regulation, and memory. Increasing evidence indicates that dysregulation of glutamatergic neurotransmission plays a crucial role in both the development and persistence of PTSD. Glutamate, the primary excitatory neurotransmitter in the central nervous system (CNS), is essential for synaptic plasticity and the formation of traumarelated memories. The aim of this study was to provide an integrated and critical synthesis of current knowledge on glutamatergic dysfunction in PTSD, with particular emphasis on its neurobiological, clinical, and therapeutic implications. This article is a narrative review of the literature published between 2017 and 2025 was conducted. Databases such as PubMed, Scopus, and Web of Science were searched for experimental, clinical, and neuroimaging studies investigating glutamatergic signaling in PTSD. The reviewed studies indicate that chronic stress disrupts glutamate homeostasis, leading to increased extracellular glutamate concentrations and impaired synaptic clearance. These alterations result in excessive activation of ionotropic receptors, particularly N-methyl-D-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, promoting calcium influx and neuronal dysfunction. Such processes affect key brain regions, including the amygdala, hippocampus, and prefrontal cortex, contributing to impaired fear extinction and heightened emotional reactivity. Importantly, glutamatergic dysregulation does not occur in isolation but interacts dynamically with neuroinflammatory pathways, altered inhibitory transmission, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In conclusion, altered glutamatergic neurotransmission represents a central mechanism in PTSD pathophysiology. Its role in synaptic plasticity, neuronal vulnerability, and network dysregulation highlights its potential relevance as a diagnostic and therapeutic target. Future research should focus on integrating glutamate-related biomarkers with mechanism-based therapeutic interventions in order to improve diagnostic precision and treatment outcomes in PTSD.