Astrocytic Regulation of Glutamate Homeostasis in the Central Nervous System: From Mechanistic Insights to Therapeutic Interventions

Abstract

Extracellular glutamate homeostasis is tightly regulated to maintain synaptic stability, and its disruption underlies diverse pathologies of the central nervous system. Here, we investigated two distinct conditions, developmental cannabinoid exposure and acute systemic immune challenge, that converge on dysregulation of tonic glutamate balance in the hippocampus. In a developmental model, prenatal exposure to Δ⁹‑tetrahydrocannabinol (Δ⁹‑THC) vapor elevated tonic glutamate levels, impaired evoked release, and reduced clearance during adolescence, accompanied by sex‑ and region‑specific alterations in presynaptic markers (VGLUT1, synaptophysin) and astrocytic GLT‑1/GFAP ratios. These findings implicate combined presynaptic and clearance mechanisms in excitatory imbalance following prenatal cannabinoid exposure. In a neuroimmune model, peripheral administration of polyinosinic‑polycytidylic acid (PIC) induced sustained hippocampal glutamate elevation, selective cytokine release (IL‑6, TNF‑α, CCL2, CCL4, CSF3), and sickness behavior. Genetic deletion or pharmacological inhibition of the cystine-glutamate antiporter xCT abolished glutamate elevation and suppressed cytokine induction, confirming xCT as a mechanistic link between immune activation and excitatory dysregulation. Novel xCT‑targeting compounds further reduced extracellular glutamate, highlighting xCT as a chemically tractable therapeutic target. Together, these complementary models demonstrate that developmental and inflammatory insults converge on glutamate imbalance through distinct neuronal and glial pathways, underscoring the vulnerability of hippocampal excitatory homeostasis and identifying potential avenues for intervention in hyperexcitatory and neuroinflammatory conditions.