Abstract
Translation of synaptic mRNA contributes to alterations in the proteome necessary to consolidate long-term potentiation (LTP), a model of memory processes. Yet, how this process is controlled is not fully resolved. MicroRNAs are non-coding RNAs that negatively regulate gene expression by suppressing translation or promoting mRNA degradation. As specific microRNAs are synaptically located, we hypothesized that they are ideally suited to couple synaptic activation, translational regulation, and LTP persistence. The aim of this study was to identify LTP-regulated microRNAs at or near synapses. Accordingly, LTP was induced unilaterally at perforant path-dentate gyrus synapses in awake adult Sprague-Dawley rats. Five hours later, dentate gyrus middle molecular layer neuropil, containing potentiated synapses, was laser-microdissected. MicroRNA expression profiling, using TaqMan Low Density MicroRNA Microarrays (n = 4), identified eight regulated microRNAs. Subsequent individual TaqMan assays confirmed upregulation of miR-23a-3p (1.30 ± 0.10; p = 0.015) and miR-151-3p (1.17 ± 0.19; p = 0.045) in a second cohort (n = 7). Interestingly, bioinformatic analysis indicated that miR-151-3p and miR-23a-3p regulate synaptic reorganisation and transcription, respectively. In summary, we have demonstrated for the first time that microRNAs are regulated in isolated neuropil following LTP induction in vivo, supporting the hypothesis that synaptic, LTP-responsive microRNAs contribute to LTP persistence via regulation of the synaptic proteome.
Highlights
Long-term potentiation (LTP) is a form of synaptic plasticity whereby high-frequency stimulation (HFS) induces a long-lasting enhancement of synaptic transmission
Induction of robust LTP in the perforant path of freely moving adult rats As we have shown previously using whole dentate gyrus that specific miRNA levels are altered 5 h post-LTP induction, here we focused on this timepoint
To test our hypothesis that miRNAs are regulated in the middle molecular layer (MML) neuropil that includes potentiated synapses 5 h after LTP induction, we carried out miRNA expression profiling of matched LTP-stimulated and control MML tissue using TaqMan Low Density microRNA Arrays (TLDAs) (n = 4; Fig 2)
Summary
Long-term potentiation (LTP) is a form of synaptic plasticity whereby high-frequency stimulation (HFS) induces a long-lasting enhancement of synaptic transmission. Our recent genomewide expression profiling studies showed that the LTP-related transcriptional response extends much further than the immediate period following LTP expression: mRNAs are differentially expressed up to at least 24 h later [6, 7]. These LTP-regulated gene networks appear to be subject to a variety of regulatory systems, including post-transcriptional control by microRNAs (miRNAs) [6]. MiRNAs were predicted to function as hub molecules in LTP-related gene networks 5 h and 24 h after LTP induction and we and others have shown that the levels of miRNA are altered in response to plasticity [6, 8,9,10,11,12,13]
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