Abstract
We measured the expression of 187 miRNAs using quantitative real time PCR in the hippocampal CA1 region of contextually conditioned mice and cultured embryonic rat hippocampal neurons after neuronal stimulation with either NMDA or bicuculline. Many of the changes in miRNA expression after these three types of stimulation were similar. Surprisingly, the expression level of half of the 187 measured miRNAs was changed in response to contextual conditioning in an NMDA receptor-dependent manner. Genes that control miRNA biogenesis and components of the RISC also exhibited activity induced expression changes and are likely to contribute to the widespread changes in the miRNA profile. The widespread changes in miRNA expression are consistent with the finding that genes up-regulated by contextual conditioning have longer 3′ UTRs and more predicted binding sites for miRNAs. Among the miRNAs that changed their expression after contextual conditioning, several inhibit inhibitors of the mTOR pathway. These findings point to a role for miRNAs in learning and memory that includes mTOR-dependent modulation of protein synthesis.
Highlights
Ever since new protein synthesis was proposed as a requirement for memory formation [1], many different molecular mechanisms related to transcription, translation and post-translational modifications have been implicated in learning and memory [2]
At each of three different time points, the median coefficient of variation was 0.32–0.36 (p,10214, KruskalWallis test, Figure 1D). This indicates that contextual conditioning changes miRNA expression, and the effect lasts at least 24 hours
Contextual conditioning, we observed that about half of the profiled miRNAs underwent changes in their CA1 hippocampal expression from 1 h to 24 h after contextual conditioning. These changes were similar in amplitude to the response of in vitro cultured rat embryonic hippocampal neurons after chemical stimulation with NMDA or bicuculline
Summary
Ever since new protein synthesis was proposed as a requirement for memory formation [1], many different molecular mechanisms related to transcription, translation and post-translational modifications have been implicated in learning and memory [2]. Synaptic plasticity and memory storage require precise regulation of gene expression and spatiotemporally constrained protein synthesis near synaptic sites [3]. MicroRNAs (miRNAs) are small non-coding RNA molecules that can dampen the expression of specific proteins by binding to the 39-untranslated regions (UTR) of their target genes [4,5]. These miRNA-mRNA duplexes are housed within the RNAinduced silencing complex (RISC). MiRNAs regulate a broad range of cellular functions, such as stem cell maintenance [9], cellular differentiation [10,11], synaptic plasticity [12,13] and learning and memory processes [14] Each miRNA can regulate protein levels, often by small amounts, encoded by hundreds of genes directly or indirectly [7,8]. miRNAs regulate a broad range of cellular functions, such as stem cell maintenance [9], cellular differentiation [10,11], synaptic plasticity [12,13] and learning and memory processes [14]
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