Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase

Javier Sanchez-Padilla; Jaime N. Guzman; Ema Ilijic; Jyothisri Kondapalli; Daniel J. Galtieri; Ben Yang; Simon Schieber; Wolfgang Oertel; David Wokosin; Paul T. Schumacker; D. James Surmeier

doi:10.1038/nn.3717

Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase

Javier Sanchez-Padilla, Jaime N. Guzman, Ema Ilijic, Jyothisri Kondapalli, Daniel J. Galtieri, Ben Yang, Simon Schieber, Wolfgang Oertel, David Wokosin, Paul T. Schumacker, D. James Surmeier^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

Abstract

Loss of noradrenergic locus coeruleus (LC) neurons is a prominent feature of aging-related neurodegenerative diseases, such as Parkinson's disease (PD). The basis of this vulnerability is not understood. To explore possible physiological determinants, we studied LC neurons using electrophysiological and optical approaches in ex vivo mouse brain slices. We found that autonomous activity in LC neurons was accompanied by oscillations in dendritic Ca ²⁺ concentration that were attributable to the opening of L-type Ca²⁺ channels. This oscillation elevated mitochondrial oxidant stress and was attenuated by inhibition of nitric oxide synthase. The relationship between activity and stress was malleable, as arousal and carbon dioxide increased the spike rate but differentially affected mitochondrial oxidant stress. Oxidant stress was also increased in an animal model of PD. Thus, our results point to activity-dependent Ca²⁺ entry and a resulting mitochondrial oxidant stress as factors contributing to the vulnerability of LC neurons.

Original language	English (US)
Pages (from-to)	832-840
Number of pages	9
Journal	Nature neuroscience
Volume	17
Issue number	6
DOIs	https://doi.org/10.1038/nn.3717
State	Published - Jun 2014

ASJC Scopus subject areas

Neuroscience(all)

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@article{15b6e13078ab44dfb6e6fd95dcd1231f,

title = "Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase",

abstract = "Loss of noradrenergic locus coeruleus (LC) neurons is a prominent feature of aging-related neurodegenerative diseases, such as Parkinson's disease (PD). The basis of this vulnerability is not understood. To explore possible physiological determinants, we studied LC neurons using electrophysiological and optical approaches in ex vivo mouse brain slices. We found that autonomous activity in LC neurons was accompanied by oscillations in dendritic Ca 2+ concentration that were attributable to the opening of L-type Ca2+ channels. This oscillation elevated mitochondrial oxidant stress and was attenuated by inhibition of nitric oxide synthase. The relationship between activity and stress was malleable, as arousal and carbon dioxide increased the spike rate but differentially affected mitochondrial oxidant stress. Oxidant stress was also increased in an animal model of PD. Thus, our results point to activity-dependent Ca2+ entry and a resulting mitochondrial oxidant stress as factors contributing to the vulnerability of LC neurons.",

author = "Javier Sanchez-Padilla and Guzman, {Jaime N.} and Ema Ilijic and Jyothisri Kondapalli and Galtieri, {Daniel J.} and Ben Yang and Simon Schieber and Wolfgang Oertel and David Wokosin and Schumacker, {Paul T.} and Surmeier, {D. James}",

note = "Funding Information: We acknowledge the technical help of S. Ulrich, Y. Chen, L. Fisher and K. Chen. We acknowledge S. Chan (Northwestern University) for supplying qPCR primer sets and J.T. Walter (Northwestern University) for supplying GP recordings. This work was supported by the JPB and IDP Foundations, US National Institutes of Health grants NS047085 (D.J.S.), NS054850 (D.J.S.), K12GM088020 (J.S.-P.), HL35440 (P.T.S.) and RR025355 (P.T.S.), and Department of Defense contracts W81XWH-07-1-0170 and W23RYX-2150-N601 (D.J.S.). The authors gratefully thank the laboratory of T. Dawson (Johns Hopkins University) for providing DJ-1−/− mice.",

year = "2014",

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doi = "10.1038/nn.3717",

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AU - Sanchez-Padilla, Javier

AU - Guzman, Jaime N.

AU - Ilijic, Ema

AU - Kondapalli, Jyothisri

AU - Galtieri, Daniel J.

AU - Yang, Ben

AU - Schieber, Simon

AU - Oertel, Wolfgang

AU - Wokosin, David

AU - Schumacker, Paul T.

AU - Surmeier, D. James

N1 - Funding Information: We acknowledge the technical help of S. Ulrich, Y. Chen, L. Fisher and K. Chen. We acknowledge S. Chan (Northwestern University) for supplying qPCR primer sets and J.T. Walter (Northwestern University) for supplying GP recordings. This work was supported by the JPB and IDP Foundations, US National Institutes of Health grants NS047085 (D.J.S.), NS054850 (D.J.S.), K12GM088020 (J.S.-P.), HL35440 (P.T.S.) and RR025355 (P.T.S.), and Department of Defense contracts W81XWH-07-1-0170 and W23RYX-2150-N601 (D.J.S.). The authors gratefully thank the laboratory of T. Dawson (Johns Hopkins University) for providing DJ-1−/− mice.

PY - 2014/6

Y1 - 2014/6

N2 - Loss of noradrenergic locus coeruleus (LC) neurons is a prominent feature of aging-related neurodegenerative diseases, such as Parkinson's disease (PD). The basis of this vulnerability is not understood. To explore possible physiological determinants, we studied LC neurons using electrophysiological and optical approaches in ex vivo mouse brain slices. We found that autonomous activity in LC neurons was accompanied by oscillations in dendritic Ca 2+ concentration that were attributable to the opening of L-type Ca2+ channels. This oscillation elevated mitochondrial oxidant stress and was attenuated by inhibition of nitric oxide synthase. The relationship between activity and stress was malleable, as arousal and carbon dioxide increased the spike rate but differentially affected mitochondrial oxidant stress. Oxidant stress was also increased in an animal model of PD. Thus, our results point to activity-dependent Ca2+ entry and a resulting mitochondrial oxidant stress as factors contributing to the vulnerability of LC neurons.

AB - Loss of noradrenergic locus coeruleus (LC) neurons is a prominent feature of aging-related neurodegenerative diseases, such as Parkinson's disease (PD). The basis of this vulnerability is not understood. To explore possible physiological determinants, we studied LC neurons using electrophysiological and optical approaches in ex vivo mouse brain slices. We found that autonomous activity in LC neurons was accompanied by oscillations in dendritic Ca 2+ concentration that were attributable to the opening of L-type Ca2+ channels. This oscillation elevated mitochondrial oxidant stress and was attenuated by inhibition of nitric oxide synthase. The relationship between activity and stress was malleable, as arousal and carbon dioxide increased the spike rate but differentially affected mitochondrial oxidant stress. Oxidant stress was also increased in an animal model of PD. Thus, our results point to activity-dependent Ca2+ entry and a resulting mitochondrial oxidant stress as factors contributing to the vulnerability of LC neurons.

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Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase

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