Abstract
The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies1,2. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.
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Acknowledgements
We thank R. Jaenisch and M. Rios for providing BDNF knockout frozen brains, L. Guarente and D. Cohen for providing SIRT1Δ and SIRT1 knockout mice, Y. Shi for providing the plasmids expressing YY1 and YY1 shRNA, A. Mungenast for manuscript editing, K. Singh and M. Dobbin for critical reading of the manuscript, M. Dobbin for help with Supplementary Fig. 5, X. Ge for help with model illustration, and N. Joseph for help with mouse colony maintenance. This work is partially supported by an NIH grant, PO1 AG027916, to L.-H.T.; W.-Y.W. is supported by a Postdoctoral Fellowship from the Simons Foundation; J.Gr. is supported by a Prospective Researchers Fellowship from the Swiss National Science Foundation; J.Gao is supported by the Howard Hughes Medical Institute. L.-H.T. is an investigator of the Howard Hughes Medical Institute.
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L.-H.T. designed, directed and coordinated the project. J.Gao designed and performed electrophysiological recordings, behaviour tests, biochemical assays and morphological analyses; W.-Y.W. contributed to the design and generation of microRNA constructs, and performed viral injections, behaviour tests and biochemical analyses; Y.-W.M., J.Gao and L.P. performed luciferase assays and biochemical analyses; J.Gr. and G.M. performed behaviour tests; S.C.S. contributed to viral injection; D.K. contributed to SIRT1 plasmid construction. The manuscript was written by J.Gao, D.K., S.C.S., W.-Y.W. and L.-H.T. and commented on by all the authors.
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Gao, J., Wang, WY., Mao, YW. et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105–1109 (2010). https://doi.org/10.1038/nature09271
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DOI: https://doi.org/10.1038/nature09271
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