Reactive astrocytes contribute to neurological disorders; however, the functional phenotypes of reactive astrocytes are poorly identified. Reactive astrocytes exhibit dysregulated Ca²⁺ dynamics, which can have detrimental effects on synapses and neurons in various neurological disorders. Several molecules involved in Ca²⁺ dysregulation have been identified in astrocytes. Our focus has been on the P2Y1 receptor (P2Y1R), which is activated by extracellular ATP or ADP and is implicated in neurological disorders like epilepsy, stroke, and Alzheimer's disease. To investigate the pathophysiological significance of P2Y1R upregulation in astrocytes and its downstream molecules, we utilized transgenic mice with astrocyte-specific overexpression of P2Y1R using the Tet-Off system (P2Y1OE). We focused mainly on the hippocampus and performed behavioral analysis, EEG, electrophysiology, two-photon Ca²⁺ imaging, RNA-seq, and immunohistochemistry. Our findings revealed that 1) P2Y1OE leads to neuronal hyperexcitability by enhancement of astrocyte-neuron interaction, 2) P2Y1OE increases IGFBP2 expression, which enhances neuronal excitation, and 3) P2Y1R and IGFBP2 co-upregulate in disease models, such as epilepsy and stroke. Overall, P2Y1R-IGFBP2 signaling may contribute to neuronal hyperexcitability in several neurological disorders.