Cerebellar Epigenetics: Transcription of MicroRNAs in Purkinje Cells

Abstract

Climbing fiber activity is often associated with cerebellar plasticity. However, seemingly simple and short-lasting examples of neuronal plasticity such as Long-Term Potentiation (LTP) are associated with the translation and translocation of as many as 100 proteins. One means of controlling protein translation is through the interaction of microRNAs with mRNAs. MicroRNAs are small non-coding nucleotides that repress translation of mRNAs with complementary nucleotide sequences. A single microRNA may share nucleotide complementarity with as many as 30 different mRNAs, enhancing the scope of its regulatory impact. While microRNAs play an important role in cellular development, apoptosis and microbial defense, the role of microRNAs in the regulation of neuronal activity in adult nervous systems has been unexplored. Possibly, translation of many proteins necessary for neuronal plasticity is regulated by the repressive action of only a few microRNAs. Here we consider how the transcription of microRNAs in cerebellar Purkinje cells is influenced by activation of its climbing fiber synapses. We use horizontal optokinetic stimulation (HOKS) to chronically regulate climbing fiber excitation of floccular Purkinje cells in mice for 0–30 h. We investigate how this activity influences the transcription of microRNAs in Purkinje cells with enhanced climbing fiber signals compared to Purkinje cells with merely spontaneous climbing fiber inputs. HOKS evokes increases in 12 microRNA transcripts in floccular Purkinje cells. One of these microRNAs, miR335, increases 18-fold after 24 h of HOKS. After HOKS is stopped, miR335 transcripts decay with a time constant of ~2.5 h. HOKS evokes a 28-fold increase in pri-miR335 transcripts. These data indicate that the evoked increase in mature miR335 transcripts can be attributed to increased transcription of microRNAs.