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

被引：5

作者：

Pulcrano, Salvatore ^{[1
]}

De Gregorio, Roberto ^{[1
,2
]}

De Sanctis, Claudia ^{[1
,3
]}

Volpicelli, Floriana ^{[1
,4
]}

Piscitelli, Rosa Maria ^{[5
]}

Speranza, Luisa ^{[6
]}

Perrone-Capano, Carla ^{[1
,4
]}

di Porzio, Umberto ^{[1
]}

Caiazzo, Massimiliano ^{[7
,8
]}

Martini, Alessandro ^{[5
]}

Giacomet, Cecilia ^{[5
]}

Medina, Diego ^{[9
,10
]}

Awatramani, Rajeshwar ^{[11
]}

Viggiano, Davide ^{[12
]}

Federici, Mauro ^{[5
]}

Mercuri, Nicola B. ^{[5
,13
]}

Guatteo, Ezia ^{[5
,14
]}

Bellenchi, Gian Carlo ^{[1
,5
]}

机构：

[1] CNR, Inst Genet & Biophys, I-80131 Naples, Italy

[2] Weill Cornell Med & New York Presbyterian, Caryl & Israel Englander Inst Precis Med, New York, NY 10021 USA

[3] Neuropathol Brain Bank Mt Sinai, New York, NY 10029 USA

[4] Univ Naples Federico II, Sch Med & Surg, Dept Pharm, I-80131 Naples, Italy

[5] Fdn Santa Lucia Ist Ricovero & Cura Carattere Sci, I-00143 Rome, Italy

[6] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, New York, NY 10461 USA

[7] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy

[8] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, NL-3584 CG Utrecht, Netherlands

[9] Telethon Inst Genet & Med, I-80078 Pozzuoli, Italy

[10] Univ Naples Federico II, Dept Med & Translat Sci, I-80131 Naples, Italy

[11] Northwestern Univ, Dept Neurol, Chicago, IL 60611 USA

[12] Univ Campania L Vanvitelli, Dept Translat Med Sci, I-80131 Naples, Italy

[13] Univ Tor Vergata, Dept Syst Med, I-00133 Rome, Italy

[14] Parthenope Univ, Dept Motor Sci & Wellness, I-80133 Naples, Italy

来源：

JOURNAL OF NEUROSCIENCE | 2023年 / 43卷 / 48期

基金：

美国国家卫生研究院;

关键词：

conditional KO; dopamine; excitability; miR-218; miRNAs; substantia nigra; EMBRYONIC STEM-CELLS; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; IN-VITRO; MIDBRAIN; EXPRESSION; MOUSE; TARGET; SPECIFICATION; MODULATION;

D O I：

10.1523/JNEUROSCI.0431-23.2023

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：8104 / 8125

页数：22