Microglial galectin-3 disrupts parvalbumin interneurons and hippocampal synchrony, driving cognitive deficits.

Sepsis-associated encephalopathy (SAE), a devastating neurological complication of systemic inflammation, affects approximately 70% of patients with sepsis. It not only increases mortality but also leaves survivors with persistent cognitive deficits. However, the mechanisms underlying SAE progression remain incompletely understood. Here, using a lipopolysaccharide (LPS)-induced mouse model of SAE, we identify microglial galectin-3 (Gal-3) as a central pathogenic mediator driving systemic inflammation-induced cognitive impairment. Mechanistically, systemic LPS challenge robustly upregulates microglial Gal-3, which in turn activates Toll-like receptor 2 (TLR2) signaling and promotes NLRP3/AIM2 inflammasome assembly. This microglia-driven inflammatory cascade substantially exacerbates local oxidative stress, leading to selective structural and functional impairment of hippocampal parvalbumin (PV) interneurons. Dysfunction of these critical interneurons disrupts theta/gamma oscillations, impairs excitatory/inhibitory (E/I) balance and synaptic plasticity, and ultimately results in severe cognitive decline. Supporting this pathogenic cascade, pharmacological inhibition of Gal-3 with TD139 effectively suppresses TLR2/inflammasome activation, attenuates oxidative stress, and prevents memory deficits. Conversely, targeted rAAV-mediated overexpression of Gal-3 in microglia is sufficient to recapitulate neuroinflammation, PV-interneuron injury, oscillatory abnormalities, and cognitive impairment. Finally, chemogenetic reactivation of hippocampal PV interneurons using DREADDs restores theta/gamma oscillations and ameliorates LPS-induced cognitive deficits. Together, our findings define a coherent pathogenic axis linking microglial Gal-3 upregulation to PV interneuron-dependent network desynchronization and highlight Gal-3 as a promising therapeutic target for inflammation-associated cognitive disorders.