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

Nat Neurosci. 2014 Jun;17(6):832-40. doi: 10.1038/nn.3717. Epub 2014 May 11.


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 Ca(2+) 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 Ca(2+) entry and a resulting mitochondrial oxidant stress as factors contributing to the vulnerability of LC neurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium Channels, L-Type / physiology
  • Dendrites / enzymology*
  • Enzyme Activation / physiology
  • Locus Coeruleus / cytology
  • Locus Coeruleus / enzymology*
  • Locus Coeruleus / metabolism
  • Male
  • Membrane Potential, Mitochondrial / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / enzymology*
  • Mitochondria / metabolism
  • Nitric Oxide Synthase / physiology*
  • Oxidative Stress / physiology*


  • Calcium Channels, L-Type
  • Nitric Oxide Synthase