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

The klotho gene family consists of alpha-, beta-, and gamma-Kiotho, which encode type I single-pass transmembrane proteins with large extracellular domains. alpha-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 alpha-Klotho leads to a phenotype that resembles accelerated aging, as the expression level of the alpha-Klotho protein in the hippocampal formation of mice decreases with age. Here, we show that intrahippocampal viral expression of secreted human alpha-Klotho alters social behavior and memory formation. Interestingly, overexpression of secreted human alpha-Klotho in the CA1 changed the nest-building behavior and improved object recognition, object location and passive avoidance memory. Moreover, alpha-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 alpha-Klotho.