Stress-induced neuroinflammation and synaptic dysregulation: Linking HPA axis to glutamate and NMDA receptors

Chronic stress is a major risk factor for psychiatric and neurological disorders, operating through interconnected molecular cascades that link neuroendocrine dysfunction to synaptic pathology. This review mechanistically examines how stress-induced hypothalamic-pituitary-adrenal (HPA) axis hyperactivation sustains glucocorticoid release, driving microglial activation and astrocytic reactivity toward pro-inflammatory phenotypes characterized by immunometabolic reprogramming. Key inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and quinolinic acid (QUIN) derived from the upregulated kynurenine pathway (KP)- impair glutamate homeostasis by compromising astrocytic reuptake and promoting excitotoxic extrasynaptic N-methyl-d-aspartate receptor (NMDAR) signaling. These pathological alterations disrupt synaptic plasticity through modified NMDAR subunit composition, impaired long-term potentiation (LTP), and complement cascade-mediated synaptic pruning, establishing a self-perpetuating cycle of vulnerability particularly within the hippocampus and prefrontal cortex. Consequently, by elucidating these interconnected pathways reveals promising therapeutic targets, including microglial phenotype modulators, NMDAR-specific interventions, and integrated pharmacological and non-pharmacological strategies aimed at restoring synaptic homeostasis and circuit function. Ultimately, this review maps these biological pathways to outline protective interventions against the physical damage of chronic stress, offering a roadmap for new treatments to restore healthy neural connections and brain function.