This study investigates the role of SIRT1 in memory and synaptic plasticity, focusing on a novel microRNA-mediated mechanism. SIRT1, a NAD-dependent deacetylase, is known for its roles in longevity, cardiac function, DNA repair, and genomic stability. The authors demonstrate that SIRT1 modulates synaptic plasticity and memory formation through the regulation of miR-134, a brain-specific microRNA. SIRT1 activation enhances synaptic plasticity, while its loss impairs it. This impairment is mediated by post-transcriptional regulation of CREB expression via miR-134. SIRT1 normally limits miR-134 expression through a repressor complex containing the transcription factor YY1. When SIRT1 is deficient, miR-134 levels rise, leading to down-regulated expression of CREB and BDNF, which in turn impairs synaptic plasticity. The findings highlight a novel role for SIRT1 in cognition and a previously unknown microRNA-based mechanism of SIRT1 regulation, suggesting potential therapeutic targets for CNS disorders.This study investigates the role of SIRT1 in memory and synaptic plasticity, focusing on a novel microRNA-mediated mechanism. SIRT1, a NAD-dependent deacetylase, is known for its roles in longevity, cardiac function, DNA repair, and genomic stability. The authors demonstrate that SIRT1 modulates synaptic plasticity and memory formation through the regulation of miR-134, a brain-specific microRNA. SIRT1 activation enhances synaptic plasticity, while its loss impairs it. This impairment is mediated by post-transcriptional regulation of CREB expression via miR-134. SIRT1 normally limits miR-134 expression through a repressor complex containing the transcription factor YY1. When SIRT1 is deficient, miR-134 levels rise, leading to down-regulated expression of CREB and BDNF, which in turn impairs synaptic plasticity. The findings highlight a novel role for SIRT1 in cognition and a previously unknown microRNA-based mechanism of SIRT1 regulation, suggesting potential therapeutic targets for CNS disorders.