Astrocytic LCN2 contributes to neuroinflammation-associated cognitive impairment through dual disruption of excitatory/inhibitory balance.

Neuroinflammation is a major contributor to cognitive dysfunction, yet the astrocyte-derived signals linking inflammatory stress to hippocampal dysfunction remain incompletely understood. Using a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation, this study identifies lipocalin-2 (LCN2) as an important astrocytic mediator of hippocampal dysfunction. LPS upregulates hippocampal LCN2, induces cognitive impairment, and increases inflammatory cytokine expression. Astrocyte-specific LCN2 knockdown alleviates LPS-induced cognitive impairment and reduces astrocyte reactivity. In vivo extracellular recordings show that astrocytic LCN2 knockdown restores LPS-suppressed firing of putative pyramidal neurons. At the synaptic level, LCN2 knockdown attenuates dendritic spine loss, lysosomal expansion in reactive astrocytes, astrocyte-associated accumulation of excitatory synaptic markers, and reduced miniature excitatory postsynaptic current frequency. In parallel, LPS induces astrocytic GABA accumulation, monoamine oxidase B upregulation, and enhanced tonic GABAergic inhibition without significantly altering phasic inhibitory transmission. Astrocytic LCN2 knockdown also improves CA1 pyramidal neuron excitability and rescues hippocampal long-term potentiation. Together, these findings identify astrocytic LCN2 as an important mediator linking excitatory synaptic injury with enhanced tonic inhibition during neuroinflammation-associated cognitive impairment.