Neonatal 6-OHDA lesion of the SNc induces striatal compensatory sprouting from surviving SNc dopaminergic neurons without VTA contribution

Abstract

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) are uniquely vulnerable to neurodegeneration in Parkinsons disease (PD). We hypothesize that their large axonal arbor is a key factor underlying their vulnerability, due to increased bioenergetic, proteostatic and oxidative stress. In keeping with this model, other DAergic populations with smaller axonal arbors are mostly spared during the course of PD and are more resistant to experimental lesions in animal models. Aiming to improve mouse PD models, we examined if neonatal partial SNc lesions could lead to adult mice with fewer SNc DA neurons that are endowed with larger axonal arbors because of compensatory mechanisms. We injected 6-hydroxydopamine (6-OHDA) unilaterally in the SNc at an early postnatal stage at a dose selected to induce loss of approximately 50% of SNc DA neurons. We find that at 10- and 90-days after the lesion, the axons of SNc DA neurons show massive compensatory sprouting, as revealed by the proportionally smaller decrease in tyrosine hydroxylase (TH) in the striatum compared to the loss of SNc DA neuron cell bodies. The extent and origin of this axonal sprouting was further investigated by AAV-mediated expression of eYFP in SNc or ventral tegmental area (VTA) DA neurons of adult mice. Our results reveal that SNc DA neurons have the capacity to substantially increase their axonal arbor size and suggest that mice designed to have reduced numbers of SNc DA neurons could potentially be used to develop better mouse models of PD, with elevated neuronal vulnerability. Graphical abstract textO_LIWe describe a technique to induce the loss of approximately 50% of SNc DA neurons in neonate mice using unilateral intranigral 6-OHDA (left panel). C_LIO_LICompensatory axonal sprouting was observed in the striatum as early as 10 days following the lesion (at P15), with effects lasting until adulthood (P90). C_LIO_LIConditional AAV-mediated expression of eYFP (green) reveals SNc DA neurons, projecting to the dorsal striatum (middle panel), and not VTA DA neurons, projecting to the ventral striatum (right panel), as the main source of compensatory axonal sprouting. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/437271v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@5febf7org.highwire.dtl.DTLVardef@17cc625org.highwire.dtl.DTLVardef@b4d509org.highwire.dtl.DTLVardef@e496a_HPS_FORMAT_FIGEXP M_FIG C_FIG