Induction of Lewy-like aggregates perturbs the firing dynamics of midbrain dopaminergic neurons in vivo

Lewy-bodies are protein aggregates that are thought to lead to neurodegeneration in Parkinson’s disease. However, little is known about the contributions of these aggregates to the symptomatology of the disease. We injected alpha-synuclein pre-formed fibrils (PFFs) into dorsolateral striatum to induce Lewy-like aggregates in substantia nigra dopamine neurons and examined the effects 1- and 3-months post-injection, stages that are prior to overt cell loss. Aggregate-bearing dopamine neurons exhibited an increase in burst-firing in vivo and their firing became synchronized with cortical activity. Aggregates had a progressive effect on dopamine neuron activity, with a decrease in firing rate observed 3-months after PFF injection. In addition to altered neuronal firing, PFFs caused a reduction in evoked dopamine release and in the rate of dopamine uptake measured in striatal slices. Furthermore, alpha-synuclein aggregates were detected in dopaminergic axons in striatum and a loss of these axons was observed prior to cell body degeneration. These findings suggest that at early stages of disease, Lewy-like aggregates cause loss of dopaminergic axons and alter both the rate and pattern of dopamine neuron firing. Thus, aggregates may not only be instrumental in neurodegeneration, but may also play a role in the symptoms of Parkinson’s disease.