Vesicular glutamate transporter VGLUT2 expression emerges in substantia nigra dopamine neurons in mouse models of parkinsonism in the absence of neurodegeneration

Abstract Background and Purpose Subsets of midbrain dopamine (DA) neurons express the vesicular glutamate transporter VGLUT2 and can release the excitatory neurotransmitter glutamate. VGLUT2 + DA neurons of the substantia nigra pars compacta (SNc) were shown to be more resistant to neurodegeneration in animal models of Parkinson's disease (PD). Additionally, there is evidence that VGLUT2 + DA neurons are enriched in the SNc of patients with PD, suggesting that VGLUT2 expression may confer resilience to DA neurons not only in animal models but also in the human disease. It remains unclear whether VGLUT2 + DA neurons are simply selected over VGLUT2 − DA neurons during degeneration or whether VGLUT2 can also emerge de novo upon neuronal stress or injury. Experimental Approach We employed pharmacological models of reversible parkinsonism to determine whether acute DA depletion or DA receptor antagonism would increase VGLUT2 + DA neurons in the SNc. Additionally, we isolated striatal synaptic vesicles from Parkinsonian mice to test how glutamate affected vesicular DA uptake. Key Results We found that acute depletion of DA or antagonism of D 2 receptors sufficed to increase the fraction of DA neurons expressing VGLUT2, suggesting that VGLUT2 can emerge in DA neurons de novo . Increased VGLUT2 expression resulted in enhanced vesicular DA uptake in the presence of glutamate. Conclusions and Implication Our work provides evidence that VGLUT2 expression is induced in DA neurons under conditions of hypodopaminergia or D 2 receptor antagonism. VGLUT2 emergence in DA neurons may be a compensatory strategy when DA levels are low and/or DA receptor signalling is compromised.