Repressing Repressors to Make Memories

Science Signaling  31 Aug 2010:
Vol. 3, Issue 137, pp. ec263
DOI: 10.1126/scisignal.3137ec263

MicroRNAs have been implicated in the molecular mechanisms of memory formation. Gao et al. show that in mice the NAD-dependent deacetylase SIRT1 limits the abundance of a specific microRNA, miR-134, which inhibits the translation of CREB, a transcription factor needed for synaptic long-term potentiation (LTP) and hippocampal memory formation. Mice with a brain-specific knockout of SIRT1 showed impaired memory formation in multiple paradigms and failed to exhibit LTP in hippocampal CA1 neurons. Although the SIRT1-deficient mice had grossly normal brains, staining for dendrites and functional synapses revealed a decrease in dendritic spine density and presynaptic nerve terminals in the hippocampus. The abundance of CREB was reduced in the hippocampi of SIRT1-deficient mice, as was binding of CREB to the promoter regions of the gene encoding brain-derived neurotrophic factor (BDNF), which is required for synaptic plasticity. Analysis of the microRNA profile of wild-type and SIRT1-deficient hippocampi revealed eight microRNAs with altered abundance, and miR-134 was chosen for further analysis because it had been identified previously as a negative regulator of dendritic spine formation. In a series of experiments with reporter constructs and transfected CAD cells (a neural cell line), the authors showed that miR-134 decreased CREB activity and that SIRT1 bound to regulatory regions in the pre–miR-134 sequence to inhibit its transcription. Chromatin immunoprecipitation experiments indicated that SIRT1 and YY1 both bound to the pre–miR-134 sequence, and binding of SIRT1 in cultured cells was reduced if YY1 was knocked down. LTP and memory formation were analyzed in mice in which miR-134 or a locked–nucleic acid (LNA)–modified oligonucleotide probe that knocks down miR-134 was delivered with a lentivirus into the CA1 area. Overexpression of miR-134 abolished LTP and impaired hippocampal-mediated memory formation, whereas introduction of the LNA–miR-134 into the SIRT1-deficient mice restored LTP and contextual fear memory. Thus, the transcriptional repressors SIRT1 and YY1 limit the accumulation of the translational repressor miR-134 to allow CREB to function in memory formation.

J. Gao, W.-Y. Wang, Y.-W. Mao, J. Gräff, J.-S. Guan, L. Pan, G. Mak, D. Kim, S. C. Su, L.-H. Tsai, A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105–1109 (2010). [PubMed]