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

Neuropharmacology. 2018 Mar 15:131:291-303. doi: 10.1016/j.neuropharm.2017.12.037. Epub 2017 Dec 22.


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.

Keywords: Calcium/calmodulin-dependent protein kinase II; Long-term potentiation; Memory deficit; Na(+)/Ca(2+) exchangers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / psychology
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism*
  • CA1 Region, Hippocampal / pathology
  • Calcineurin / metabolism
  • Calcineurin Inhibitors / pharmacology
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / metabolism*
  • Cognitive Dysfunction / pathology
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology
  • Humans
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology
  • Male
  • Memory / physiology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • RNA, Messenger / metabolism
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism*
  • Synapses / metabolism
  • Synapses / pathology
  • Tacrolimus / pharmacology


  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Calcineurin Inhibitors
  • RNA, Messenger
  • Slc8a2 protein, mouse
  • Slc8a3 protein, mouse
  • Sodium-Calcium Exchanger
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcineurin
  • Calcium
  • Tacrolimus