Infectious vs. Sterile Neuroinflammation: Differential Consequences on Neuronal Circuitry

Neuroinflammation constitutes a key modulator of synaptic function and neuronal network organization, with direct implications for cognition, emotion, and behavior. However, a conceptual gap persists in understanding how the origin of the inflammatory stimulus—infectious or sterile—and, in particular, the temporal trajectory of the neuroimmune response determine divergent functional outcomes at the circuit level. In this narrative review, evidence from experimental models and translational studies is integrated to analyze the mechanisms through which neuroinflammation modulates synaptic plasticity, excitation–inhibition balance, and network efficiency. The reviewed data indicate that neuroinflammation induced by infectious stimuli is typically characterized by acute glial activation, intense but predominantly reversible network dysfunction, and transient functional alterations, mediated by proinflammatory cytokines and dynamic changes in neuronal excitability. In contrast, sterile neuroinflammation and unresolved inflammatory states are associated with sustained glial activation, complement-dependent synaptic remodeling, microglial priming, and persistent circuit dysfunction, with long-lasting effects on plasticity and cognitive performance. Prolonged microglia–astrocyte interactions emerge as a critical determinant in the transition from reversible functional alterations to states of chronic circuit disconnection. Taken together, this review proposes that the functional outcome of neuroinflammation depends less on the initial origin of the stimulus than on the duration, resolution, and inflammatory memory of the neuronal circuit. These findings underscore the need for experimental approaches that integrate temporal and circuit-level dimensions to understand the contribution of neuroinflammation to persistent brain dysfunction and neurodegenerative vulnerability.