Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons

Abstract Dopamine neurons in the substantia nigra pars compacta and ventral tegmental area regulate behaviours such as reward-related learning, and motor control. Dysfunction of these neurons is implicated in Schizophrenia, addiction to drugs, and Parkinson’s disease. While some dopamine neurons fir...

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Autores principales:	Rajeshwari Iyer, Mark A. Ungless, Aldo A. Faisal
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7151f096159f4937af6d0970815a517c
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spelling	oai:doaj.org-article:7151f096159f4937af6d0970815a517c2021-12-02T15:05:30ZCalcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons10.1038/s41598-017-05578-52045-2322https://doaj.org/article/7151f096159f4937af6d0970815a517c2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05578-5https://doaj.org/toc/2045-2322Abstract Dopamine neurons in the substantia nigra pars compacta and ventral tegmental area regulate behaviours such as reward-related learning, and motor control. Dysfunction of these neurons is implicated in Schizophrenia, addiction to drugs, and Parkinson’s disease. While some dopamine neurons fire single spikes at regular intervals, others fire irregular single spikes interspersed with bursts. Pharmacological inhibition of calcium-activated potassium (SK) channels increases the variability in their firing pattern, sometimes also increasing the number of spikes fired in bursts, indicating that SK channels play an important role in maintaining dopamine neuron firing regularity and burst firing. However, the exact mechanisms underlying these effects are still unclear. Here, we develop a biophysical model of a dopamine neuron incorporating ion channel stochasticity that enabled the analysis of availability of ion channels in multiple states during spiking. We find that decreased firing regularity is primarily due to a significant decrease in the AHP that in turn resulted in a reduction in the fraction of available voltage-gated sodium channels due to insufficient recovery from inactivation. Our model further predicts that inhibition of SK channels results in a depolarisation of action potential threshold along with an increase in its variability.Rajeshwari IyerMark A. UnglessAldo A. FaisalNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rajeshwari Iyer Mark A. Ungless Aldo A. Faisal Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons
description	Abstract Dopamine neurons in the substantia nigra pars compacta and ventral tegmental area regulate behaviours such as reward-related learning, and motor control. Dysfunction of these neurons is implicated in Schizophrenia, addiction to drugs, and Parkinson’s disease. While some dopamine neurons fire single spikes at regular intervals, others fire irregular single spikes interspersed with bursts. Pharmacological inhibition of calcium-activated potassium (SK) channels increases the variability in their firing pattern, sometimes also increasing the number of spikes fired in bursts, indicating that SK channels play an important role in maintaining dopamine neuron firing regularity and burst firing. However, the exact mechanisms underlying these effects are still unclear. Here, we develop a biophysical model of a dopamine neuron incorporating ion channel stochasticity that enabled the analysis of availability of ion channels in multiple states during spiking. We find that decreased firing regularity is primarily due to a significant decrease in the AHP that in turn resulted in a reduction in the fraction of available voltage-gated sodium channels due to insufficient recovery from inactivation. Our model further predicts that inhibition of SK channels results in a depolarisation of action potential threshold along with an increase in its variability.
format	article
author	Rajeshwari Iyer Mark A. Ungless Aldo A. Faisal
author_facet	Rajeshwari Iyer Mark A. Ungless Aldo A. Faisal
author_sort	Rajeshwari Iyer
title	Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons
title_short	Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons
title_full	Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons
title_fullStr	Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons
title_full_unstemmed	Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons
title_sort	calcium-activated sk channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/7151f096159f4937af6d0970815a517c
work_keys_str_mv	AT rajeshwariiyer calciumactivatedskchannelscontrolfiringregularitybymodulatingsodiumchannelavailabilityinmidbraindopamineneurons AT markaungless calciumactivatedskchannelscontrolfiringregularitybymodulatingsodiumchannelavailabilityinmidbraindopamineneurons AT aldoafaisal calciumactivatedskchannelscontrolfiringregularitybymodulatingsodiumchannelavailabilityinmidbraindopamineneurons
_version_	1718388837704531968

Calcium-activated SK channels control firing regularity by modulating sodium channel availability in midbrain dopamine neurons

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