Aberrant Amygdala-Dependent Cued Fear Memory in Na⁺/Ca²⁺ Exchanger 1 Heterozygous Mice

Na⁺/Ca²⁺ exchangers (NCXs) are mainly expressed in the plasma membrane and exchange one Ca²⁺ for three Na⁺, depending on the electrochemical gradients across the plasma membrane. NCXs have three isoforms, NCX1-3, encoded by distinct genes in mammals. Here, we report that heterozygous mice lacking NCX1 (NCX1^+/-) exhibit impaired amygdala-dependent cued fear memory. NCX1^+/- mice showed significant impairment in fear-related behaviors measured with the elevated-plus maze, light-dark, open-field, and marble-burying tasks. In addition, NCX1^+/- mice showed abnormality in cued fear memory but not in contextual fear memory in a fear-conditioning task. In immunohistochemical analyses, NCX1^+/- mice had significantly increased number of c-Fos-positive cells in the lateral amygdala (LA) but not in the central amygdala following fear-related tone stimuli. c-Fos expression peaked at 1 h. In concordance with the aberrant fear-related behaviors in NCX1^+/- mice, enhanced long-term potentiation was also observed in the LA of these mice. Furthermore, enhancement of CaMKII or CaMKIV activity in the LA was observed in NCX1^+/- mice by immunoblot analyses. In contrast, CaMKII^+/- but not CaMKIV^-/- mice insufficiently exhibited tone-induced cued fear memory and there was no increase in the number of c-Fos-positive cells in the LA. Altogether, the increased CaMKII activity and consequent c-Fos expression likely account for the dysregulation of amygdala-dependent cued fear memory in NCX1^+/- mice.