the sirt1 ko and sirt1/nestin - cre mice were provided by the laboratory of leonard guarente . the plasmids and lna - mirna ( ambion ) were transfected into mouse cad cells using lipofectamine 2000 ( invitrogen ) according to the manufacturer s instructions . rna extraction , purification , and quantitative pcr were performed according to the manufacturer 's protocols . tissue and cell lysis , protein concentrations , and western blot analyses were prepared as described previously5 . immunoblot data were quantified by measuring the band intensity with nih imaging software and un - scan - it gel digitizing software ( silk scientific ) . immunostaining was performed as described previously3 with lsmeta10 software and a confocal microscope ( zeiss ) . two - way anova was used to compare differences between groups at several time points .
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 , appears 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 plays 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 , while its loss - of - function impairs , synaptic plasticity . 
 surprisingly , these effects were mediated via post - transcriptional regulation of 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 down - regulated expression of creb and bdnf , thereby impairing synaptic plasticity . 
 these findings demonstrate a novel 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 signaling , 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 cns disorders .