This study investigates the role of hippocampal astrocytes in cognitive decline and neuroinflammation. Using optogenetic and chemogenetic tools, the researchers found that repeated stimulation of hippocampal CA1 astrocytes in mice induced cognitive impairment, reduced synaptic long-term potentiation (LTP), and activated inflammatory astrocytes. Mechanistically, lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and cognitive impairment by decreasing LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes produced similar results, while a metabolic inhibitor of astrocytes attenuated these phenomena. Fiber photometry revealed high levels of hippocampal astrocyte activation in the neuroinflammation model. The findings suggest that reactive astrocytes in the hippocampus are sufficient and necessary to induce cognitive decline through LCN2 release and synaptic modulation, highlighting the importance of abnormal glial-neuron interactions in the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.This study investigates the role of hippocampal astrocytes in cognitive decline and neuroinflammation. Using optogenetic and chemogenetic tools, the researchers found that repeated stimulation of hippocampal CA1 astrocytes in mice induced cognitive impairment, reduced synaptic long-term potentiation (LTP), and activated inflammatory astrocytes. Mechanistically, lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and cognitive impairment by decreasing LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes produced similar results, while a metabolic inhibitor of astrocytes attenuated these phenomena. Fiber photometry revealed high levels of hippocampal astrocyte activation in the neuroinflammation model. The findings suggest that reactive astrocytes in the hippocampus are sufficient and necessary to induce cognitive decline through LCN2 release and synaptic modulation, highlighting the importance of abnormal glial-neuron interactions in the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.