Englander Institute for Precision Medicine

miR-218 Promotes Dopaminergic Differentiation and Controls Neuron Excitability and Neurotransmitter Release through the Regulation of a Synaptic-Related Genes Network.

TitlemiR-218 Promotes Dopaminergic Differentiation and Controls Neuron Excitability and Neurotransmitter Release through the Regulation of a Synaptic-Related Genes Network.
Publication TypeJournal Article
Year of Publication2023
AuthorsPulcrano S, De Gregorio R, De Sanctis C, Volpicelli F, Piscitelli RMaria, Speranza L, Perrone-Capano C, di Porzio U, Caiazzo M, Martini A, Giacomet C, Medina D, Awatramani R, Viggiano D, Federici M, Mercuri NB, Guatteo E, Bellenchi GCarlo
JournalJ Neurosci
Volume43
Issue48
Pagination8104-8125
Date Published2023 Nov 29
ISSN1529-2401
KeywordsAnimals, Cell Differentiation, Dopamine, Dopaminergic Neurons, Female, Male, Mice, MicroRNAs, Neurotransmitter Agents
Abstract

In the brain, microRNAs (miRNAs) are believed to play a role in orchestrating synaptic plasticity at a higher level by acting as an additional mechanism of translational regulation, alongside the mRNA/polysome system. Despite extensive research, our understanding of the specific contribution of individual miRNA to the function of dopaminergic neurons (DAn) remains limited. By performing a dopaminergic-specific miRNA screening, we have identified miR-218 as a critical regulator of DAn activity in male and female mice. We have found that miR-218 is specifically expressed in mesencephalic DAn and is able to promote dopaminergic differentiation of embryonic stem cells and functional maturation of transdifferentiated induced DA neurons. Midbrain-specific deletion of both genes encoding for miR-218 (referred to as miR-218-1 and mir218-2) affects the expression of a cluster of synaptic-related mRNAs and alters the intrinsic excitability of DAn, as it increases instantaneous frequencies of evoked action potentials, reduces rheobase current, affects the ionic current underlying the action potential after hyperpolarization phase, and reduces dopamine efflux in response to a single electrical stimulus. Our findings provide a comprehensive understanding of the involvement of miR-218 in the dopaminergic system and highlight its role as a modulator of dopaminergic transmission.SIGNIFICANCE STATEMENT In the past decade, several miRNAs have emerged as potential regulators of synapse activity through the modulation of specific gene expression. Among these, we have identified a dopaminergic-specific miRNA, miR-218, which is able to promote dopaminergic differentiation and regulates the translation of an entire cluster of synapse related mRNAs. Deletion of miR-218 has notable effects on dopamine release and alters the intrinsic excitability of dopaminergic neurons, indicating a direct control of dopaminergic activity by miR-218.

DOI10.1523/JNEUROSCI.0431-23.2023
Alternate JournalJ Neurosci
PubMed ID37816598
PubMed Central IDPMC10697421
Grant ListR01 NS119690 / NS / NINDS NIH HHS / United States

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