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

Noradrenergic neurons in the locus coeruleus (LC) are known to undergo degeneration in Parkinson's and Alzheimer's diseases. LC neurons may be under bioenergetic constraints due to spontaneous spiking. Here, Sanchez-Padilla et al . show that calcium entry through L-type channels during spiking of LC neurons creates mitochondrial oxidant and nitrosative stress. The study also demonstrates increased LC vulnerability in a mouse model of Parkinson's disease. 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.