Immune-mediated excitotoxicity in brain disorders

Balanced activity of neuronal and immune networks is essential for maintaining central nervous system (CNS) function and mental health, whereas disturbances in network dynamics often lead to excitotoxicity and progressive pathology across brain diseases. Emerging evidence indicates that immune-mediated mechanisms can shape excitotoxic injury at least as profoundly as classical glutamatergic transmission. Here, we extend the concept of excitotoxicity beyond glutamate receptor overactivation to include innate and adaptive immune pathways, introducing the framework of immune-mediated excitotoxicity. We focus on three illustrative settings: epilepsy and ischaemic injury, where reiterative feedback between neuronal excitation and neuroimmune activation promotes acute excitotoxic damage; neurodegenerative disorders, in which misfolded protein aggregates act as immune stressors that amplify local inflammation; and multiple sclerosis, characterized by persistent, compartmentalized inflammation that drives chronic excitotoxic cycles. Across these examples, we define three hallmarks - feedback, stressor and chronicity - as organizing principles of this paradigm and describe the dynamic communication between neuronal and immune networks that underlies immune-mediated excitotoxicity. Recognizing these neuroimmune interactions as central to CNS homeostasis and - when perturbed - to disease opens up new avenues for therapeutic intervention targeting immune-mediated excitotoxicity.