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Na+/Ca2+ exchangers (NCXs) are expressed primarily in the plasma membrane of most cell types, where they mediate electrogenic exchange of one Ca2+ for three Na+ ions, depending on Ca2+ and Na+ electrochemical gradients across the membrane. Three mammalian NCX isoforms (NCX1, NCX2, and NCX3) are each encoded by a distinct gene. Here, we report that NCX2 and NCX3 protein and mRNA levels are relatively reduced in hippocampal CA1 of APP23 and APP-KI mice. Likewise, NCX2+/− or NCX3+/− mice exhibited impaired hippocampal LTP and memory-related behaviors. Moreover, relative to controls, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in NCX2+/− mouse hippocampus but increased in hippocampus of NCX3+/− mice. NCX2 or NCX3 heterozygotes displayed impaired maintenance of hippocampal LTP, a phenotype that in NCX2+/− mice was correlated with elevated calcineurin activity and rescued by treatment with the calcineurin (CaN) inhibitor FK506. Likewise, FK506 treatment significantly restored impaired hippocampal LTP in APP-KI mice. Moreover, Ca2+ clearance after depolarization following high frequency stimulation was slightly delayed in hippocampal CA1 regions of NCX2+/− mice. Electron microscopy revealed relatively decreased synaptic density in CA1 of NCX2+/− mice, while the number of spines with perforated synapses in CA1 significantly increased in NCX3+/− mice. We conclude that memory impairment seen in NCX2+/− and NCX3+/− mice reflect dysregulated hippocampal CaMKII activity, which alters dendritic spine morphology, findings with implications for memory deficits seen in Alzheimer's disease model mice.The mRNA and protein levels of NCX2 and NCX3 in CA1 significantly reduced in APP23 and APP-KI mouse brain.NCX2+/− or NCX3+/− mice exhibited impaired memory-related behaviors.NCX2+/− and NCX3+/− mice dysregulated hippocampal CaMKII activity.