Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida 33477, USA.
J Neurosci. 2013 Jan 23;33(4):1734-40. doi: 10.1523/JNEUROSCI.2873-12.2013.
De novo protein synthesis supports long-lasting functional and structural plasticity and is a molecular requirement for new memory formation. Recent evidence has suggested that microRNAs may be involved in regulating the molecular mechanisms underlying neural plasticity. MicroRNAs are endogenous, noncoding RNAs capable of post-transcriptional repression of their mRNA targets. To explore the potential for microRNA-mediated regulation of amygdala-dependent memory formation, we performed expression profiling of microRNAs in the lateral amygdala of rats 1 h after auditory fear conditioning. Microarray analysis revealed that over half of all known microRNAs are endogenously expressed in the lateral amygdala, with 7 microRNAs upregulated and 32 downregulated by auditory fear training. Bioinformatic analysis identified several of the downregulated microRNAs as potential repressors of actin-regulating proteins known to be involved in plasticity and memory. Downregulation of one of these microRNAs by auditory fear conditioning, miR-182, was confirmed by quantitative real-time PCR. Overexpression of miR-182 within the lateral amygdala resulted in decreased expression of the protein but not mRNA of two synapse-enriched regulators of actin known to modulate structural plasticity, cortactin and Rac1. The overexpression of miR-182 also disrupted long-term but not short-term auditory fear memory. These data indicate that learning-induced suppression of miR-182, a microRNA previously uncharacterized in the brain, supports long-term memory formation in the amygdala and suggests it does so, at least in part, through the derepression of key actin-regulating proteins. These findings further indicate that microRNAs may represent a previously underappreciated mechanism for regulating protein synthesis during memory consolidation.
从头蛋白质合成支持长期功能和结构可塑性，是新记忆形成的分子要求。最近的证据表明，microRNAs 可能参与调节神经可塑性的分子机制。microRNAs 是内源性的非编码 RNA，能够在后转录水平抑制其 mRNA 靶标。为了探索 microRNA 介导的调节杏仁核依赖性记忆形成的潜力，我们在听觉恐惧条件反射后 1 小时对大鼠外侧杏仁核中的 microRNAs 进行了表达谱分析。微阵列分析显示，所有已知的 microRNAs 中有一半以上在外侧杏仁核中内源性表达，有 7 个 microRNAs 被听觉恐惧训练上调，32 个下调。生物信息学分析确定了一些下调的 microRNAs 作为已知参与可塑性和记忆的肌动蛋白调节蛋白的潜在抑制剂。通过听觉恐惧条件反射下调的一个 microRNA，miR-182，通过定量实时 PCR 得到了证实。在外侧杏仁核中过表达 miR-182 导致两种富含突触的肌动蛋白调节蛋白的蛋白而非 mRNA 表达降低，这两种蛋白是已知调节结构可塑性的蛋白，分别为 cortactin 和 Rac1。miR-182 的过表达也破坏了长期而非短期的听觉恐惧记忆。这些数据表明，学习诱导的 miR-182 抑制，一种以前在大脑中未被描述的 microRNA，支持杏仁核中的长期记忆形成，并表明它至少部分通过关键肌动蛋白调节蛋白的去抑制来实现。这些发现进一步表明，microRNAs 可能代表了在记忆巩固过程中调节蛋白质合成的一个以前未被充分认识的机制。
