Aberrant activation of hippocampal astrocytes causes neuroinflammation and cognitive decline in mice. Jae-Hong Kim and colleagues investigated the role of hippocampal CA1 astrocytes in cognitive decline using optogenetic and chemogenetic tools. Their findings show that repeated optogenetic stimulation of hippocampal CA1 astrocytes leads to cognitive impairment and reduced synaptic long-term potentiation (LTP) in mice, accompanied by the appearance of inflammatory astrocytes. Mechanistic studies using knockout models and neuronal cultures revealed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediates neuroinflammation and cognitive impairment by decreasing LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes produced similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP showed high levels of hippocampal astrocyte activation in the neuroinflammation model. The study suggests that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial-neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions. The research highlights the critical role of astrocytes in cognitive function and neuroinflammation, with LCN2 playing a key role in the pathogenesis of cognitive decline. LCN2 deficiency ameliorates neuroinflammation and cognitive impairment after optogenetic stimulation of hippocampal astrocytes. The study also shows that sustained Gq signaling activation of hippocampal CA1 astrocytes mimics the effects of optogenetic stimulation, including LCN2 release, neuroinflammation, and cognitive deficits. These findings provide new insights into the mechanisms underlying neuroinflammation and cognitive decline associated with astrocyte dysfunction.Aberrant activation of hippocampal astrocytes causes neuroinflammation and cognitive decline in mice. Jae-Hong Kim and colleagues investigated the role of hippocampal CA1 astrocytes in cognitive decline using optogenetic and chemogenetic tools. Their findings show that repeated optogenetic stimulation of hippocampal CA1 astrocytes leads to cognitive impairment and reduced synaptic long-term potentiation (LTP) in mice, accompanied by the appearance of inflammatory astrocytes. Mechanistic studies using knockout models and neuronal cultures revealed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediates neuroinflammation and cognitive impairment by decreasing LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes produced similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP showed high levels of hippocampal astrocyte activation in the neuroinflammation model. The study suggests that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial-neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions. The research highlights the critical role of astrocytes in cognitive function and neuroinflammation, with LCN2 playing a key role in the pathogenesis of cognitive decline. LCN2 deficiency ameliorates neuroinflammation and cognitive impairment after optogenetic stimulation of hippocampal astrocytes. The study also shows that sustained Gq signaling activation of hippocampal CA1 astrocytes mimics the effects of optogenetic stimulation, including LCN2 release, neuroinflammation, and cognitive deficits. These findings provide new insights into the mechanisms underlying neuroinflammation and cognitive decline associated with astrocyte dysfunction.