Synaptic alterations in the hippocampus of an animal model of progressive parkinsonism and the effect of dopaminergic treatments

Resumen

This Ph.D. project is focused on the characterization of pathological events in the hippocampus, which could be related to non-motor manifestation in Parkinson¿s disease such as behavioral and memory impairments. For that purpose, we have studied the temporal sequence of functional and structural changes in the hippocampus in a rat model of progressive parkinsonism induced by the overexpression of human ¿-synuclein (h¿-syn) with the A53T mutation (AAV-h¿-syn) in the substantia nigra compacta (SNpc). We observed a progressive h¿-syn overexpression in the SNpc and the adjacent ventral tegmental area (VTA) associated with dopaminergic neuron degeneration in both nuclei. Moreover, h¿-syn was also expressed in the glutamatergic neurons of the VTA, which together with the dopaminergic neurons, project to the hippocampus modulating hippocampal function and memory processes. In the hippocampus, we observed a progressive h¿-syn expression within the different afferent pathways from the VTA (dopaminergic, glutamatergic and GABAergic pathways) since the earliest stages after theAAV-h¿-syn inoculation. Furthermore, AAV-h¿-syn inoculated animals showed a trend towards decreased performance in a hippocampal-dependent memory task, which was concomitant to the onset of nigral dopaminergic degeneration and motor impairment. Interestingly, long-term potentiation (LTP), the cellular mechanism for memory storage, was already impaired in the hippocampal synapse since the beginning of h¿-syn expression, probably through increasing basal synaptic transmission. The dopaminergic agonist pramipexole (PPX) and the dopamine precursor L-DOPA restored hippocampal LTP in the AAV-h¿-syn animals, although the latter was only effective at the latest time point evaluated. This might be explained by the compromised intracellular transport and synaptic vesicle trafficking observed by using a proteomics approach and suggesting a deficient neurotransmitter release at the earliest time points after the AAV-h¿-syn inoculation. By contrast, at the latest time point after the AAV-h¿-syn inoculation, deregulated proteins in isolated hippocampal synapses are involved in homeostatic processes such as the regulation of calcium levels, membrane potential, and receptor-mediated signaling pathways. Finally, with an in vivo PET study, we found decreased glucose metabolism in the hippocampus of animals with an established dopaminergic lesion chronically treated with PPX. Overall, we show that progressive synucleinopathy is associated with early synaptic dysfunction in the hippocampus and defective memory, providing an excellent model for the development of disease modifying new synapse-targeted therapies for Parkinson¿s disease.