Sci. Signal., 31 August 2010
Neuroscience Repressing Repressors to Make Memories
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
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]
Citation: N. R. Gough, Repressing Repressors to Make Memories. Sci. Signal. 3, ec263 (2010).
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