“Regulation of microRNA (miRNA) expression and function in


“Regulation of microRNA (miRNA) expression and function in the context of activity-dependent 26s Proteasome structure synaptic plasticity in the adult brain is little understood. Here, we examined miRNA expression during long-term potentiation

(LTP) in the dentate gyrus of adult anesthetized rats. Microarray expression profiling identified a subpopulation of regulated mature miRNAs 2 h after the induction of LTP by high-frequency stimulation (HFS) of the medial perforant pathway. Real-time polymerase chain reaction analysis confirmed modest upregulation of miR-132 and miR-212, and downregulation of miR-219, while no changes occurred at 10 min post-HFS. Surprisingly, pharmacological blockade of N-methyl-d-aspartate receptor (NMDAR)-dependent LTP enhanced expression of these mature miRNAs. This HFS-evoked expression was abolished by local infusion of the group 1 metabotropic glutamate receptor (mGluR) antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA). AIDA had no effect on LTP induction or maintenance, but blocked activity-dependent depotentiation of LTP. Turning to the analysis of miRNA precursors, we show that HFS elicits 50-fold elevations of primary (pri) and precursor (pre) miR-132/212 that is transcription dependent and mGluR dependent, but insensitive to NMDAR blockade. Primary miR-219 expression was unchanged during LTP. In situ hybridization showed upregulation of the pri-miR-132/212 Vadimezan cluster

restricted to dentate granule cell somata. Thus, HFS induces transcription miR-132/212 that is mGluR dependent and functionally correlated with depotentiation rather than LTP. In contrast, NMDAR activation selectively downregulates mature miR-132, -212 and -219 levels, indicating accelerated decay of these mature miRNAs. This study demonstrates

differential regulation of primary and mature miRNA expression by mGluR and NMDAR signaling following LTP induction, the function of which remains to be defined. Excitatory synapses of the mammalian brain display diverse forms of activity-dependent synaptic plasticity (Bliss et al., 2007; Nelson & Turrigiano, 2008). Bursts of synaptic activity can induce short-term changes in synaptic strength, but more stable modifications typically require modulation of gene expression at the transcriptional and post-transcriptional levels. Through post-transcriptional regulation, synaptic activity may dictate the time and place of neuronal protein synthesis Hydroxychloroquine datasheet (Ashraf & Kunes, 2006; Sutton & Schuman, 2006; Bramham & Wells, 2007; Bramham et al., 2010). Recently, microRNAs (miRNAs) have entered the fray as major regulators of post-transcriptional gene expression. miRNAs are short (19–24 nucleotides) non-coding RNAs that most commonly inhibit protein synthesis by sequence-specific binding to the 3′untranslated region (3′ UTR) of target mRNAs and recruitment of an RNA-induced silencing complex (RISC), resulting in reduced translation or mRNA degradation (Standart & Jackson, 2007; Filipowicz et al., 2008).

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