Reduced CaM Kinase II and CaM Kinase IV Activities Underlie Cognitive Deficits in NCKX2 Heterozygous Mice
Among five members of the K+-dependent Na+/Ca2+ exchanger (NCKX) family (NCKX1–5), only NCKX2 is highly expressed in mouse brain. NCKX2 in plasma membranes mediates cytosolic calcium excretion through electrogenic exchange of 4 Na+ for 1 Ca2+ and 1 K+. Here, we observed significantly decreased levels of NCKX2 protein and mRNA in the CA1 region of APP23 mice, a model of Alzheimer’s disease. We also found that, like APP23 mice, heterozygous NCKX2-mutant mice exhibit mildly impaired hippocampal LTP and memory acquisition, the latter based on novel object recognition and passive avoidance tasks. When we addressed underlying mechanisms, we found that both CaMKII autophosphorylation and CaMKIV phosphorylation significantly decreased in CA1 regions of NCKX2+/− relative to control mice. Likewise, phosphorylation of GluA1 (Ser-831) and CREB (Ser-133), respective downstream targets of CaMKII and CaMKIV, also significantly decreased in the CA1 region. BDNF protein and mRNA levels significantly decreased in CA1 of NCKX2+/− relative to control mice. Finally, CaN activity increased in CA1 of NCKX2+/− mice. Our findings suggest that like APP23 mice, NCKX2+/− mice may exhibit impaired learning and hippocampal LTP due to decreased CaM kinase II and CaM kinase IV activities.
KeywordsK+-dependent Na+/Ca2+ exchangers Cognition Calcium/calmodulin-dependent protein kinase II Long-term potentiation Hippocampus
Brain-derived neurotrophic factor
Calcium/calmodulin-dependent protein kinase II
Calcium/calmodulin-dependent protein kinase IV
cAMP-responsive element binding protein
Extracellular signal-regulated kinase
Field excitatory post-synaptic potentials
Green fluorescent protein
K+-dependent Na+/Ca2+ exchangers
Protein phosphatase 1
This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health and Welfare of Japan (KAKENHI 22390109 to K.F.; 20790398 to S.M.; 23590319 to T.I.; 25460350 to S.K.), the Uehara Memorial Foundation (K.F.) and the Smoking Research Foundation (S.M.). We also thank Novartis Pharma for providing APP23 mice.
S.M., Y.Y., R.I., H.I., Y.S., K.S., H.T., and T.I. performed experiments. S.K., K.H., J.T., and T.I. provided NCKX2 antibody and NCKX2 knockout mice, and critical advice. S.M. and K.F. wrote the manuscript and designed the study.
Compliance with Ethical Standards
All animal protocols were approved by the Committee on Animal Experiments at Tohoku University.
Conflict of Interest
The authors declare that they have no competing interests.
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