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Aquaporin-4(AQP4)is the major water channel in adult brain and is primarily expressed in astrocytes.A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function.Astrocytes are implicated in information processing,signal transmission,and regulation of synaptic plasticity.However,the role of AQP4 in synaptic plasticity and fear extinction remains unclear.It was found that AQP-4 knockout impaired novel object recognition,and facilitated fear extinction of mice.The NMDA receptor-dependent long-term depression(LTD)was also facilitated without alter the basal synaptic transmission in the CA3-CA1 pathway in the hippocampus.Furthermore,AQP-4 knockout significantly and selectively increased NMDA receptor-mediated EPSCs.Application of NR2B selective antagonist ifenprodil and Ro256981 decreased AQP-4 knockout-induced LTD.AQP-4 knockout significantly and selectively increased NR2B-NMDA receptor mediated EPSCs.Meanwhile,NR2B receptor antagonist ifenprodil and HA966 30 min before extinction training significantly attenuated AQP-4 knockout-induced fear extinction.These findings imply a role for AQP4 in synaptic plasticity and fear extinction in the hippocampus by regulating extrasynaptic NR2B-NMDA receptor.