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Dopamine axons of substantia nigra pars compacta neurons: clues to selective vulnerability in Parkinson's disease (PD) Eleftheria K. Pissadaki1,2 and J. Paul Bolam1 1 2 MRC Anatomical Neuropharmacology Unit, Dept. Pharmacology, Oxford, OX1 3QT, UK; Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece Although mutated genes, protein aggregates, environmental toxins and other factors associated with PD are widely distributed in the nervous system and affect many classes of neurons, dopamine (DA) neurons of the substantia nigra pars compacta (SNc) show exceptional and selective vulnerability. One factor that distinguishes SNc DA neurons from other DA neurons is their massive axonal arbour and the massive number of synapses they establish. We propose that the high energy cost of such a massive axonal architecture puts SNc DA neurons energetically ‘on the edge’ such that any DA neuron-specific or non-specific stressor, puts them into negative energy balance, eventually leading to cell death. We calculated the energy cost of the propagation of axon potentials and maintenance of axonal membrane potential of rat SNc DA neurons, ventral tegmental area DA neurons which are less vulnerable in PD and human SNc DA neurons which are 10 times more complex than in the rat. We implemented a compartmental model of the DA neurons with synthetically reconstructed axon arbourisations. After the model's reliability was ensured, we inferred the cost of axon potential propagation and membrane repolarization from the fluxes of sodium and calcium ions. We found that different degrees of calcium conductance along the axon branches strongly influences the firing frequency as well as the sodium conductance needed to attain signal transmission, when bounded by SNc DA neuron conduction velocity. Furthermore, the energy cost is exponentially related to the size and degree of branching of the axonal field in a full binary axon tree. We conclude that the size and complexity of the axons of SNc DA neuron puts them under an excessive energy demand that may contribute to their selective vulnerability in PD.