Axonal domain structure as a putative identifier of neuron-specific vulnerability to oxidative stress in cultured neurons

Abstract

Several populations of neurons are purported to degenerate in Parkinson’s disease (PD). One current hypothesis suggests that vulnerable neurons in PD share common characteristics including projecting to voluminous territories and having extremely long and branched axonal domains with large numbers of neurotransmitter release sites. In this study, we used a mouse in vitro culture system to compare the axonal domain of neuronal populations suspected to be vulnerable in PD to that of neuronal populations considered at a lesser risk. In the first category, we included dopamine (DA) neurons of the substantia nigra, noradrenergic neurons of the locus coeruleus, serotonin neurons of the raphe nuclei, and cholinergic neurons of the dorsal motor nucleus of the vagus. In the second category, we included DA neurons of the ventral tegmental area, cholinergic neurons of the hypoglossal nucleus, and cholinergic interneurons of the dorsal striatum. Validating their differential vulnerability, we find that, when compared to neurons presumed to be resilient in PD, a larger proportion of neurons presumed to be vulnerable in PD degenerate in response to cell stress induced by hydrogen peroxide. We also find that they are endowed with larger axonal domains, that are more complex, have more axonal varicosities with a higher proportion of varicosities that are positive for synaptotagmin 1. Notwithstanding the obvious limitations related to the dissection of small brain nuclei and to the growth of these neurons in vitro, these findings support the hypothesis that axonal domain structure is a key characteristic of neuronal vulnerability to oxidative stress.

Significance statement

Parkinson’s disease (PD) causes the specific degeneration of a small number of neuroanatomically and neurochemically defined neuronal populations. Current hypotheses suggest that these neurons are vulnerable due to their specific physiology and morphology. In this study — using mouse primary neurons — we demonstrate that, when compared to neuronal populations that are suspected to be resilient in PD, neuronal populations that are more vulnerable in PD are more sensitive to cell stress induced by hydrogen peroxide, and that the overt length and complexity of their axonal arborizations is larger. Furthermore, vulnerable neurons show a strikingly elevated proportion of axonal varicosities that are positive for synaptotagmin1, suggesting that they contain more active axon terminals.