Sex-dependent changes in AMPAR expression and Na, K-ATPase activity in the cerebellum and hippocampus of α-Klotho-Hypomorphic mice

Aging is characterized by a functional decline in several physiological systems. α-Klotho-hypomorphic mice (Kl^−/−) exhibit accelerated aging and cognitive decline. We evaluated whether male and female α-Klotho-hypomorphic mice show changes in the expression of synaptic proteins, N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, postsynaptic density protein 95 (PSD-95), synaptophysin and synapsin, and the activity of Na⁺, K⁺-ATPase (NaK) isoforms in the cerebellum and hippocampus. In this study, we demonstrated that in the cerebellum, Kl^−/− male mice have reduced expression of GluA1 (AMPA) compared to wild-type (Kl^+/+) males and Kl^−/− females. Also, Kl−/− male and female mice show reduced ɑ2/ɑ3-NaK and Mg²⁺-ATPase activities in the cerebellum, respectively, and sex-based differences in NaK and Mg²⁺-ATPase activities in both the regions. Our findings suggest that α-Klotho could influence the expression of AMPAR and the activity of NaK isoforms in the cerebellum in a sex-dependent manner, and these changes may contribute, in part, to cognitive decline.