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

Abstract

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.

• Authors: Shigeki Moriguchi, Satomi Kita, Masahiro Fukaya, Makoto Osanai, Ryo Inagaki, Yuzuru Sasaki, Hisanao Izumi, Kyoji Horie, Junji Takeda, Takashi Saito, Hiroyuki Sakagami, Takaomi C Saido, Takahiro Iwamoto, Kohji Fukunaga
• Journal: Neuropharmacology (Neuropharmacology) Vol. 131 Pg. 291-303 (03 15 2018) ISSN: 1873-7064 [Electronic] England
• PMID: 29274751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• 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

Topics

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