Pacemaker's burden

Neurons of the locus coeruleus (LC) in the brainstem innervate various regions throughout the brain and modulate sleep, wakefulness, arousal, attention and memory. LC neurons are a major source of noradrenaline in the CNS, and these neurons fire steady and spontaneous action potentials at a relatively high frequency. These neurons, however, are also extremely vulnerable as we age, and LC neurons are lost in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Their loss may contribute to some of the symptoms of these disorders, such as excessive daytime sleepiness and memory deficits. Why is this neuronal population so vulnerable to aging and stress? A study in this issue of Nature Neuroscience provides some clues to this question and shows that the pacemaking properties of LC noradrenergic neurons may be partly responsible. On page 832, Sanchez-Padilla et al. report that the pacemaking properties of LC neurons depend on the opening of voltage-dependent calcium channels (VDCCs); although the resulting influx of calcium and dendritic calcium oscillations are necessary to maintain pacemaking, they also cause mitochondrial stress, a phenomenon that is aggravated in a mouse model of Parkinson's disease.

Sanchez-Padilla et al. used ex vivo slice electrophysiology of 3–4-week-old mice to show that LC neurons—as seen in the image with a biocytin-labeled neuron counterstained with streptavidin-conjugated to Alexa 594 (in red) overlaid on neurons immunoreactive for tyrosine hydroxylase (in black and white)—are indeed autonomous pacemakers. Using pharmacological agents, the scientists established that L-type voltage-gated calcium channels contribute to this pacemaking activity. By pharmacologically blocking mitochondrial Ca²⁺ entry via junctions between the endoplasmic reticulum and mitochondria, they found that calcium fluctuations are associated with mitochondrial oxidative stress. Previous studies by this laboratory had suggested that mitochondrial Ca²⁺ entry in dopaminergic neurons of the substantia nigra can increase mitochondrial oxidative stress. Similarly, LC neurons also exhibited an increase in mitochondrial oxidant stress (as measured by a mitochondrially targeted ratiometric redox probe) that was blocked by inhibitors of L-type VDCCs or the mitochondrial Ca²⁺ uniporter. This mitochondrial oxidative stress was exacerbated in the DJ-1 null mouse, a genetic model of early onset Parkinson's disease. Nitric oxide (NO) production was also correlated with high mitochondrial stress in LC neurons and pharmacologically blocking NO synthase activity diminished mitochondrial oxidative stress.

The activity of LC neurons is known to vary with behavioral states. During arousal, for example, an increase in LC firing is mediated by orexin (released by the hypothalamus), and subsequent noradrenaline released to various neocortical regions can sharpen attention and modulate cognitive function. Surprisingly, the current study found that exogenous orexin can attenuate mitochondrial oxidative stress of LC neurons, even though it also increased LC spontaneous spiking. This effect was, however, correlated with a reduction in the amplitude of dendritic Ca²⁺ oscillations in the LC neurons. Other extrinsic signals, such as high carbon dioxide, which increases spiking activity, increased oxidative stress in LC neurons, suggesting that pacemaking-dependent oxidative stress in the LC is subject to dynamic modulation by extrinsic signals.

This work presents some tantalizing clues as to why LC neurons may be susceptible to substantial neurodegeneration in Parkinson's disease and adds to the evidence suggesting that, although L-type calcium channels are important for maintaining autonomous spiking in some neuronal populations, they may also cause increased mitochondrial stress in these neurons. Targeting these channels may be useful to combat some of the non-motor symptoms of Parkinson's disease.