Enhanced Expression of Secreted α-Klotho in the Hippocampus Alters Nesting Behavior and Memory Formation in Mice

Abstract

The klotho gene family consists of α-, β-, and γ-Klotho, which encode type I single-pass transmembrane proteins with large extracellular domains. α-Klotho exists as a full-length membrane-bound and as a soluble form after cleavage of the extracellular domain. Due to gene splicing, a short extracellular Klotho form can be expressed and secreted. Inactivation of α-Klotho leads to a phenotype that resembles accelerated aging, as the expression level of the α-Klotho protein in the hippocampal formation of mice decreases with age. Here, we show that intrahippocampal viral expression of secreted human α-Klotho alters social behavior and memory formation. Interestingly, overexpression of secreted human α-Klotho in the CA1 changed the nest-building behavior and improved object recognition, object location and passive avoidance memory. Moreover, α-Klotho overexpression increased hippocampal synaptic transmission in response to standardized stimulation strengths, altered paired-pulse facilitation of synaptic transmission, and enhanced activity-dependent synaptic plasticity. These results indicate that memory formation benefits from an augmented level of secreted α-Klotho.

Klotho overexpression improves amyloid‐β clearance and cognition in the APP/PS1 mouse model of Alzheimer's disease

“…Dubal et al (2015) also showed that Klotho elevation in hAPP/KL mice increased NMDAR‐dependent long‐term potentiation (LTP) despite of not altering hippocampal levels of Aβ. Li et al (2019) found that secreted human Klotho altered some synaptic plasticity‐related proteins and mediated a significant increase in fEPSP slope per unit of stimulation intensity in mice. These results showed the direct regulation of Klotho itself on synaptic plasticity in mice.…”

Deregulated expression of a longevity gene, Klotho, in the C9orf72 deletion mice with impaired synaptic plasticity and adult hippocampal neurogenesis

“…Although the exact function of Klotho in the central nervous system (CNS) is not known, it has been shown to enhance N-methyl-D-aspartate receptor (NMDAR)mediated synaptic activity [12] and oligodendrocyte maturation [8]. Furthermore, Klotho has been shown to regulate hippocampal synaptic plasticity [12,26,28]. Thus, it is conceivable that ablation of C9orf72 alters the Klotho expression and affects Klotho-mediated regulation on synaptic plasticity.…”

Effect of acute noise trauma on the gene expression profile of the hippocampus

“…KL knockout mice show elevated levels of proinflammatory factors and macrophage infiltration in the choroid plexus [ 32 ]. Overexpression of the secreted form of KL in the hippocampus reverses aging-related effects and cognitive dysfunction in mice [ 33 ]. Thus, KL potentially represents a protective or therapeutic target for hippocampal or cognitive dysfunction following noise-induced hearing loss.…”