microRNAs: tiny regulators of synapse function in development and disease

Abstract

The development and function of neuronal circuits within the brain are orchestrated by sophisticated gene regulatory mechanisms. Recently, microRNAs have emerged as a novel class of small RNAs that fine-tune protein synthesis. microRNAs are abundantly expressed in the vertebrate nervous system, where they contribute to the specification of neuronal cell identity. Moreover, microRNAs also play an important role in mature neurons. This review summarizes the current knowledge about the function of microRNAs in the nervous system with special emphasis on synapse formation and plasticity. The second part of this work will discuss the potential involvement of microRNAs in neurologic diseases. The study of brain microRNAs promises to expand our understanding of the mechanisms underlying higher cognitive functions and neurologic diseases.

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Working model for the role of miRNAs in local dendritic protein synthesis and spine morphology in CNS physiology and disease. Left: Dendritic miRNA recruits the RISC to the dendritic target mRNA, thereby inhibiting protein synthesis and restricting dendritic spine growth under conditions of low synaptic activity. Middle: Synaptic activation triggers release of neurotransmitters and neurotrophic factors, whose binding to the respective receptors leads to an activation of dendritic mRNA translation, presumably via post-translational modification (e.g. phosphorylation) and subsequent inactivation of inhibitory RISC components. Enhanced synthesis of miRNA-regulated proteins results in dendritic spine growth. Right: In neurologic diseases, binding of the miRNA and(or proteins (e.g. FMRP, SMN,…) to the dendritic target mRNA might be impaired, leading to an aberrant regulation of dendritic mRNA translation. The resulting deregulated expression of disease-related proteins (e.g. Limk1, MeCP2,…) might contribute to the pathological spine phenotype observed in certain CNS disorders.