MicroRNA-132, -134, and -138: a microRNA troika rules in neuronal dendrites

Abstract

Dendritic mRNA transport and local translation in the postsynaptic compartment play an important role in synaptic plasticity, learning and memory. Local protein synthesis at the synapse has to be precisely orchestrated by a plethora of factors including RNA binding proteins as well as microRNAs, an extensive class of small non-coding RNAs. By binding to complementary sequences in target mRNAs, microRNAs fine-tune protein synthesis and thereby represent critical regulators of gene expression at the post-transcriptional level. Research over the last years identified an entire network of dendritic microRNAs that fulfills an essential role in synapse development and physiology. Recent studies provide evidence that these small regulatory molecules are highly regulated themselves, at the level of expression as well as function. The importance of microRNAs for correct function of the nervous system is reflected by an increasing number of studies linking dysregulation of microRNA pathways to neurological disorders. By focusing on three extensively studied examples (miR-132, miR-134, miR-138), this review will attempt to illustrate the complex regulatory roles of dendritic microRNAs at the synapse and their implications for pathological conditions.

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

“…Importantly, the activity of some miRNAs causes spine shrinkage, whereas that of others causes spine growth (Ceman & Saugstad, 2011). For example, miR‐134 and miR‐138 both promote spine shrinkage, while miR‐132 represses Rho GTPase‐activating protein p250GAP and promotes dendritic development and spine growth (Bicker et al , 2014). Therefore, we propose that the absence of any detectable effect on spine size caused by Ago2 knockdown can be explained by the attenuation of several silencing events promoting either spine shrinkage or spine growth, with little overall change.…”

“…A number of miRNAs have been shown to be involved in specific forms of learning and memory, and dysfunction of miRNA systems is implicated in neurological and neuropsychiatric diseases including Alzheimer's, Huntington's, schizophrenia and drug addiction (Wang et al , 2012; Kocerha et al , 2015). Furthermore, a large proportion of neuronal miRNAs are enriched in dendrites, and several have been assigned roles in modulating the local translation of specific proteins involved in excitatory synaptic transmission or in regulating the actin cytoskeleton to control the morphology of dendritic spines, which house excitatory synapses (Lippi et al , 2011; Bicker et al , 2014; Hu et al , 2014, 2015; Gu et al , 2015). …”

MicroRNAs: Small molecules with big roles in neurodevelopment and diseases

“…Transgenic overexpression of miR-132 in the forebrain impaired recognition memory (Hansen et al, 2010;Scott et al, 2012). In contrast, induced expression of endogenous miR-132 in response to a spatial memory task enhanced cognition (Hansen et al, 2013), suggests that the expression level of miR-132 is tightly regulated to control learning and memory (Bicker et al, 2014). The expression of miR-132 is dysregulated in a number of neurodevelopmental disorders (Kim et al, 2010;Klein et al, 2007;Packer et al, 2008).…”

Meet the players: local translation at the synapse

“…Recently, overexpression of miR-125b has been linked to Tau protein hyperphosphorylation through the downregulation of the phosphatases DUSP6 and PPP1CA, implicating miR-125b in the pathogenesis of sporadic Alzheimer’s disease (Banzhaf-Strathmann et al, 2014). The brain-specific miR-134 inhibits translation of the LimK1 mRNA, encoding a protein kinase that promotes dendritic spine development, when the synapse is not stimulated (Schratt et al, 2006; reviewed in Bicker et al, 2014). …”