A novel pathway regulates memory and plasticity via SIRT1 and miR-134.
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 flies. 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.
Gao
Jun
J
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Wang
Wen-Yuan
WY
Mao
Ying-Wei
YW
Gräff
Johannes
J
Guan
Ji-Song
JS
Pan
Ling
L
Mak
Gloria
G
Kim
Dohoon
D
Su
Susan C
SC
Tsai
Li-Huei
LH
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D054351:Electrical Synapses / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics*; D011485:Protein Binding; D017384:Sequence Deletion; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D035683:MicroRNAs; C551912:Mirn134 microRNA, mouse; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1