Microglia-derived metabolites as novel signaling molecules: regulating neural circuit function, behavior, and their role in psychiatric disorders

Microglia, central immune and metabolic regulators, release metabolites that act as signaling molecules into the interstitial space within the neuro-immune-metabolic axis (NIMA). This review synthesizes evidence on how microglia-derived metabolites modulate neural circuit function—affecting synaptic plasticity, network oscillations, and behavior—and how their dysregulation contributes to psychiatric disorders. We highlight the dynamic role of the interstitial space in shaping metabolite signaling and discuss therapeutic strategies targeting this axis. Reconceptualizing microglial metabolites as active circuit modulators offers novel insights into psychiatric pathophysiology and potential metabolic interventions.