TY - JOUR
T1 - miR-218 promotes dopaminergic differentiation and controls neuron excitability and neurotransmitter release through the regulation of a synaptic-related genes network
AU - Pulcrano, Salvatore
AU - De Gregorio, Roberto
AU - De Sanctis, Claudia
AU - Volpicelli, Floriana
AU - Piscitelli, Rosa Maria
AU - Speranza, Luisa
AU - Perrone-Capano, Carla
AU - Di Porzio, Umberto
AU - Caiazzo, Massimiliano
AU - Martini, Alessandro
AU - Giacomet, Cecilia
AU - Medina, Diego
AU - Awatramani, Rajeshwar
AU - Viggiano, Davide
AU - Federici, Mauro
AU - Mercuri, Nicola B.
AU - Guatteo, Ezia
AU - Bellenchi, Gian Carlo
N1 - Publisher Copyright:
Copyright © 2023 the authors.
PY - 2023/11/29
Y1 - 2023/11/29
N2 - 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 mRNAs/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.
AB - 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 mRNAs/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.
KW - dopamine
KW - miR-218
KW - neuron excitability
KW - synapse
UR - http://www.scopus.com/inward/record.url?scp=85178497622&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85178497622&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0431-23.2023
DO - 10.1523/JNEUROSCI.0431-23.2023
M3 - Article
C2 - 37816598
AN - SCOPUS:85178497622
SN - 0270-6474
VL - 43
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 48
ER -