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Life extension factor klotho regulates behavioral responses to stress via modulation of GluN2B function in the nucleus accumbens

Abstract

Klotho is a life extension factor that has the ability to regulate the function of GluN2B-containing N-methyl-d-aspartate receptors (NMDARs), whose dysfunction in the nucleus accumbens (NAc) underlies critical aspects of the pathophysiology of major depression. Here, we study the functional relevance of klotho in the pathogenesis of depression. A chronic social defeat stress paradigm, in which mice are categorized as either susceptible or unsusceptible based on their performance in a social interaction test, was used in this study. We found that the expression of klotho was largely decreased in the NAc of susceptible mice compared to control or unsusceptible mice. Genetic knockdown of klotho in the NAc induced behavioral alterations relevant to depression in naive mice, while overexpression of klotho produced an antidepressive effect in normal mice and ameliorated the behavioral responses to stress in susceptible mice. Molecularly, knockdown of klotho in the NAc resulted in selective decreases in total and synaptic GluN2B expression that were identical to those in susceptible mice. Elevation of klotho in the NAc reversed the reductions in GluN2B expressions and altered synaptic transmission and spine density in the NAc of susceptible mice. Furthermore, blockade of GluN2B with a specific antagonist abolished the beneficial effects of klotho elevation in susceptible mice. Collectively, we demonstrated that klotho in the NAc modulates behavioral responses to stress by regulating the function of GluN2B-containing NMDARs. These results reveal a novel role for klotho in the pathogenesis of depression, providing new insights into the molecular basis of major depression.

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Fig. 1: Downregulation of klotho in the NAc contributes to the behavioral responses to stress in mice.
Fig. 2: Genetic overexpression of klotho in the NAc ameliorates the behavioral responses to stress in CSDS susceptible mice.
Fig. 3: Modulation of klotho level in the NAc regulates the total and surface expression of GluN2B in both the naive and susceptible mice.
Fig. 4: Genetic overexpression of klotho in NAc restores the CSDS-induced disruption of NMDAR-dependent LTD and dendritic spines density.
Fig. 5: Treatment with GluN2B antagonist abolishes the beneficial effects of klotho elevation on behavioral responses to stress and synaptic plasticity in CSDS susceptible mice.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (82060258, 81760254, 81760256 and 81960256). It was also supported by the Jiangxi Provincial Natural Science Foundation (20202BAB206026, 20202BAB216012 and 20202BBG73022). The study also received support by grants for the Jiangxi Provincial Clinical Research Center (2020BCG74002) and the Academic and Technical Leaders of Major Disciplines Foundation (20204BCJL22049).

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Y.-J.Y., B.W. and W.W. designed the research; H.-J.W., W.-N.W., H.F., L.-E.L., J.-Q.Z., C.-N.C., Y.-H.L., S.-Z.J., J.-W.X. and Z.-M.Y. performed the research; H.-J.W., L.-E.L., and Y.-J.Y. analyzed data; and H.-J.W. and Y.-J.Y. wrote the paper.

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Correspondence to Wei Wang or Yuan-jian Yang.

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Wu, Hj., Wu, Wn., Fan, H. et al. Life extension factor klotho regulates behavioral responses to stress via modulation of GluN2B function in the nucleus accumbens. Neuropsychopharmacol. 47, 1710–1720 (2022). https://doi.org/10.1038/s41386-022-01323-3

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