| First Author | Moriguchi S | Year | 2018 |
| Journal | Neuropharmacology | Volume | 131 |
| Pages | 291-303 | PubMed ID | 29274751 |
| Mgi Jnum | J:271785 | Mgi Id | MGI:6282180 |
| Doi | 10.1016/j.neuropharm.2017.12.037 | Citation | Moriguchi S, et al. (2018) Reduced expression of Na(+)/Ca(2+) exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice. Neuropharmacology 131:291-303 |
| abstractText | Na(+)/Ca(2+) exchangers (NCXs) are expressed primarily in the plasma membrane of most cell types, where they mediate electrogenic exchange of one Ca(2+) for three Na(+) ions, depending on Ca(2+) 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, Ca(2+) 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. |
