Klotho regulates CA1 hippocampal synaptic plasticity

Abstract

Global klotho overexpression extends lifespan while global klotho-deficiency shortens it. As well, klotho protein manipulations inversely regulate cognitive function. Mice without klotho develop rapid onset cognitive impairment before they are 2 months old. Meanwhile, adult mice overexpressing klotho show enhanced cognitive function, particularly in hippocampal-dependent tasks. The cognitive enhancing effects of klotho extend to humans with a klotho polymorphism that increases circulating klotho and executive function. To affect cognitive function, klotho could act in or on the synapse to modulate synaptic transmission or plasticity. However, it is not yet known if klotho is located at synapses, and little is known about its effects on synaptic function. To test this, we fractionated hippocampi and detected klotho expression in both pre and post-synaptic compartments. We find that loss of klotho enhances both pre and post-synaptic measures of CA1 hippocampal synaptic plasticity at 5 weeks of age. However, a rapid loss of synaptic enhancement occurs such that by 7 weeks, when mice are cognitively impaired, there is no difference from wild-type controls. Klotho overexpressing mice show no early life effects on synaptic plasticity, but decreased CA1 hippocampal long-term potentiation was measured at 6 months of age. Together these data suggest that klotho affects cognition, at least in part, by regulating hippocampal synaptic plasticity.

Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

“…Since KL is not detected until late embryonic development (Takeshita et al 2004), it is unlikely that neural stem cells express KL protein. Consistent with previous reports (Clinton et al 2013; Li et al 2017), the highest expression of KL is measured in choroid plexus cells but mature neuronal layers of the hippocampus, including the dentate also express KL protein (Figure 3E). KL expression is prominent in mature neuronal processes as evidenced by a gradient of increasing KL expression with lowest KL reactivity occurring in SGZ (Figure 3E).…”

“…We measured KL’s expression profile during dentate development using mRNA isolated from wild-type (WT) hippocampi embryonic day 17 (E17) to 8 weeks of age. Using a primer/probe set to allow detection of all KL forms, we found that hippocampus achieved adult level KL expression by 3 weeks of age (Figure 1A), consistent with the reported expression of KL mRNA and protein in mature neurons (Clinton et al 2013; Li et al 2017). …”

“…Meanwhile, the volume of the WT and KO hippocampi were indistinguishable at 3 weeks, when initial dentate genesis is complete (Nicola et al 2015), and at 7 weeks when KO mice are near terminal (Figure 1B,C). Although KL is overexpressed in the hippocampus of OE mice (Dubal et al 2014; Li et al 2017), we found no hippocampal or fimbria volume change at 3 or 7 weeks of age nor were changes detected into adulthood (6 months) (Figure 1D, E). These data show that gross hippocampal development is not affected by either increasing or decreasing KL protein expression.…”

“…Mouse brain KL expression is first detected during late embryonic development (Takeshita et al 2004). The cerebrospinal fluid generating choroid plexus cells express the highest levels of KL (Kuro-o et al 1997; Li et al 2004) but lower level expression is detected in neurons throughout the brain (Kuro-o et al 1997; Clinton et al 2013; Li et al 2017). We measured KL’s expression profile during dentate development using mRNA isolated from wild-type (WT) hippocampi embryonic day 17 (E17) to 8 weeks of age.…”

Fibroblast growth factor 23 and Klotho contribute to airway inflammation

“…7a). When comparing wild type mice and klotho overexpressing mice (WT, OE) (28), the later group showed increased klotho mRNA levels in the lung, which was independent of smoke exposure (Fig. 7b).…”