A novel pathway regulates memory and plasticity via SIRT1 and miR-134

A role for SIRT1 in memory SIRT1 is a deacetylase involved in DNA repair and genomic stability that was originally identified in non-mammalian model systems as a modulator of longevity. Although it was thought to function in normal brain physiology, it was not known whether SIRT1 participates in higher-order brain functions. Gao et al . now demonstrate such a role for SIRT1: its activation enhances synaptic strength and memory formation. These SIRT1-dependent effects are regulated through a post-transcriptional mechanism involving CREB activation and miR-134 production. This interplay between SIRT1 activation, miR-134 levels and synaptic proteins constitutes a previously unrecognized mechanism of plasticity regulation, and suggests that SIRT1 activation may have therapeutic potential in neurodegenerative diseases involving cognitive impairment. The deacetylase SIRT1 has been suggested to function in normal brain physiology, but it is not known whether it participates in higher-order brain functions. These authors demonstrate a role for SIRT1 in synaptic plasticity and memory formation, with activation enhancing synaptic strength and memory formation. These effects were regulated through a post-transcriptional mechanism involving CREB activation and miR-134 production. This interplay represents another mechanism of plasticity regulation with behavioural consequences. 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 1 , 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