Reduced expression of Na+/Ca2+ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice. (15th March 2018)

• Record Type: Journal Article
• Authors: Moriguchi, Shigeki; Kita, Satomi; Fukaya, Masahiro; Osanai, Makoto; Inagaki, Ryo; Sasaki, Yuzuru; Izumi, Hisanao; Horie, Kyoji; Takeda, Junji; Saito, Takashi; Sakagami, Hiroyuki; Saido, Takaomi C.; Iwamoto, Takahiro; Fukunaga, Kohji
• Is Part Of: Neuropharmacology. Volume 131(2018)
• Page Start: 291
• Page End: 303
• Publication Date: 2018-03-15
• Subjects: Na+/Ca2+ exchangers -- Long-term potentiation -- Calcium/calmodulin-dependent protein kinase II -- Memory deficit; Aβ amyloid-β -- ACSF artificial cerebrospinal fluid -- AD Alzheimer's disease -- AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor -- CaMKII calcium/calmodulin-dependent protein kinase II -- CaMKIV calcium/calmodulin-dependent protein kinase IV -- CaN calcineurin -- DARPP-32 dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa -- DG dentate gyrus -- CREB cAMP-responsive element binding protein -- fEPSPs field excitatory postsynaptic potentials -- HFS high frequency stimulation -- LTP long-term potentiation -- L-type VGCC L-type voltage-gated Ca2+ channel -- NCXs Na+/Ca2+ exchangers -- NKCC1 Na+-K+-Cl− cotransporter isoform 1 -- NFATc3 nuclear factor of activated T-cells, cytoplasmic 3 -- NMDAR N-methyl-d-aspartate receptor -- PMCA plasma membrane Ca2+-ATPase -- PP1 protein phosphatase 1 -- PSD post synaptic density; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.12.037
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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. Highlights: 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.