Endogenous and treatment-induced neuroplasticity in mouse models of Parkinson's disease

Parkinson´s disease (PD) is an age-related neurodegenerative disorder characterized by a loss of nigral dopamine (DA) neurons that project their axons to the striatum. Striatal DA depletion causes the typical motor symptoms of PD. Another key feature of PD are intracellular protein inclusions containing alpha-synuclein within affected brain regions. L-DOPA is the most effective treatment for the symptoms of PD, although it causes debilitating long-term complications (L-DOPA-induced dyskinesia). There is a pressing need to identify therapeutic approaches that can stop or slow down the progression of PD.
The first part of this thesis aims at evaluating potential disease-modifying treatments based on stimulating the Sigma-1 receptor, an intracellular protein involved in cell repair and neuroplasticity. In the first and second study, mice sustained a lesion of nigrostriatal DA neurons using the toxin 6-OHDA, and were then treated daily with the sigma-1 receptor agonists PRE-084 (first study) or ANAVEX 2-73 (second study). Both compounds induced a gradual and substantial motor recovery over 5 weeks of treatment. This was associated with an induction of neuroplasticity markers, increased density of DA fibers, and reduced inflammation in the nigrostriatal DA pathway.
Another major aim of this thesis was to assess endogenous plasticity mechanisms in mouse models of PD during ageing. In the third study, mice sustained a 6-OHDA-lesion in young adulthood and were aged to 12 or 24 months. Other mice sustained the lesion at the advanced age of 23 months (comparable in age to a 70 year-old human being). Mice in the 12- and 24-months groups showed a spontaneous recovery of motor functions, associated with pronounced sprouting of dopaminergic and serotonergic axons into the striatum. These results reveal that ageing does not interfere with the plasticity of a damaged nigrostriatal DA pathway. However, ageing increased the susceptibility to L-DOPA-induced dyskinesia acutely after the nigrostriatal lesion.
Ageing conditions were also taken into account when studying transgenic mice overexpressing human alpha-synuclein. In these mice, ageing was associated with a progressive accumulation of alpha-synuclein in several brain regions. Despite this accumulation, the nigrostriatal DA pathway appeared structurally intact. Treatment of 18 months-old transgenic mice with the DA receptor agonist, apomorphine, induced a peculiar pattern of involuntary movements associated with abnormal regulation of ERK1/2 signaling in the striatum. We conclude that an overexpression of human alpha-synuclein can cause changes in striatal signaling even at an early symptomatic stage of PD-like pathology.
In summary, this thesis reveals that pharmacological stimulation of Sigma-1 receptors can boost neuroplasticity and promote recovery after nigrostriatal DA lesions. The second part of the thesis contributes novel findings about the relationship between behavioral impairments, PD-like pathology, and nigrostriatal plasticity in different mouse models of PD.