Plastic surgeons make millions reversing the effects of aging. Although facelifts are aesthetic procedures, turning back the clock on neuron function might be beneficial because many neurological diseases strike late in life. Now Chan et al. report protection from toxins that model Parkinson's disease in neurons that revert to juvenile pacemaking in a recent article in Nature.

Parkinson's disease selectively kills dopaminergic neurons in the substantia nigra pars compacta (SNc), resulting in tremor and the loss of voluntary movement. Why are these neurons so vulnerable? Parkinson's disease spares other dopaminergic neurons, and L-DOPA, which increases dopamine, is a therapeutic treatment. Therefore, dopamine itself is not toxic to these cells.

Adult SNc dopaminergic neurons fire action potentials at regular intervals under basal conditions and are therefore known as pacemaking cells. Most pacemaking activity is Na⁺ dependent. However, the authors blocked pacemaking in SNc dopaminergic neurons with the L-type Ca²⁺ channel blocker isradipine. The Na⁺ channel blocker tetrodotoxin blocked action potentials but not regular oscillations in membrane potential, suggesting that pacemaking is Ca²⁺ dependent in SNc dopaminergic neurons.

Unlike most L-type Ca²⁺ channels, which contain the -subunit Ca_v1.2, L-type Ca²⁺ channels in SNc dopaminergic neurons contain the -subunit Ca_v1.3, which opens at relatively hyperpolarized membrane potentials and therefore likely drives pacemaking in these cells. However, SNc dopaminergic neurons from Ca_v1.3 knockout mice showed pacemaking activity. Antagonists to hyperpolarization-activated and cyclic nucleotide gated cation (HCN) channels, which are permeable to Na⁺, but not isradipine, blocked pacemaking in these neurons and in SNc dopaminergic neurons from juvenile wild-type mice, suggesting that SNc pacemaking in juvenile mice is mediated by HCN rather than Ca²⁺ channels. In wild-type mice, the density of L-type Ca²⁺ channels and their relative contribution to pacemaking increased in SNc dopaminergic neurons with age. Although the density of HCN channels did not change, their relative contribution to pacemaking declined with age.

SNc dopaminergic neurons revert to juvenile pacemaking when L-type Ca²⁺ channels are blocked. Isradipine incubation initially stopped pacemaking activity in SNc dopaminergic neurons from adult mice. However, several hours later, these neurons began pacemaking again, and HCN channel antagonists blocked the renewed pacemaking activity.

The toxins rotenone and MPTP selectively kill SNc dopaminergic neurons and are used to model Parkinson's disease. Dendrites are particularly sensitive to rotenone. Isradipine pretreatment reduced the rotenone-induced loss of neural processes and the MPTP-induced loss of neurons in SNc. Isradipine also prevented MPTP-induced motor deficits, suggesting that isradipine may slow the progression of Parkinson's disease.

How do L-type Ca²⁺ channels increase the vulnerability of SNc dopaminergic neurons to Parkinson's disease? According to the authors, rising levels of intracellular Ca²⁺ may increase mitochondrial stress and reactive oxygen species development, synergizing with mitochondrial vulnerability induced by genetic or environmental factors.

1. Chan, C. S. et al. 'Rejuvenation' protects neurons in mouse models of Parkinson's disease. Nature 447, 1081–1086 (2007). | Article | PubMed | ISI | ChemPort |