Reduced expression of Na⁺/Ca²⁺ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice

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.