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

Neuropharmacology. 2024 Nov 1:258:110097. doi: 10.1016/j.neuropharm.2024.110097. Epub 2024 Jul 31.

Abstract

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.

Keywords: Aging; Glutamatergic receptors; K(+)-ATPase; Na(+); Synaptic proteins; α-Klotho.

MeSH terms

  • Animals
  • Cerebellum* / metabolism
  • Disks Large Homolog 4 Protein / genetics
  • Disks Large Homolog 4 Protein / metabolism
  • Female
  • Hippocampus* / metabolism
  • Klotho Proteins* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, AMPA* / genetics
  • Receptors, AMPA* / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Sex Characteristics*
  • Sodium-Potassium-Exchanging ATPase* / genetics
  • Sodium-Potassium-Exchanging ATPase* / metabolism
  • Synapsins / genetics
  • Synapsins / metabolism
  • Synaptophysin / metabolism

Substances

  • Atp1a2 protein, mouse
  • Atp1a3 protein, mouse
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • glutamate receptor ionotropic, AMPA 1
  • Klotho Proteins
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Sodium-Potassium-Exchanging ATPase
  • Synapsins
  • Synaptophysin
  • Kl protein, mouse