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Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Nigrostriatal dopamine (DA) neurons are particularly susceptible to degeneration in PD, and the concomitant loss of DA signalling in the striatum is believed to underlie the motor symptoms of PD. Transgenic rodent models expressing PD-related genes have previously revealed changes to DA synapse function as one of the earliest stages of PD progression, often preceding protein aggregation and cell death. However, such models often rely on foreign gene promoter elements that do not accurately replicate the genetic expression pattern and protein levels found in PD. This thesis explores the electrically evoked release of two monoamines, DA and 5- HT (serotonin), in mice that express wild-type human (-synuclein at a range of levels, through a bacterial artificial chromosome vector (BAC), on a mouse synuclein-null background. Potential mechanisms underlying monoamine neurotransmission deficits were also investigated. Furthermore, this thesis explored the evoked release of DA in BAC transgenic rats that express the G2019S and R1441C mutant forms of the human Leucine-rich repeat kinase 2 (LRRK2) gene. All of the models covered express PD-related genes under regulation of endogenous promoter elements, which increases the physiological relevance of gene expression pattern and levels of gene expression in comparison to transgenes with foreign promoters. Fast-scan cyclic voltammetry, using carbon fibre microelectrodes, was used to sample electrically evoked DA and 5-HT in acute brain slices. High performance liquid chromatography was used to determine DA content. Mice that express relatively high levels of human (-synuclein (SNCA-C mice), at approximately double the level ofWT mice, have a -30% deficit in evoked DA release from the dorsal striatum, but not the ventral striatum, when compared to control mice (Snca -j-). Investigations performed here showed that the DA release deficit depends on the level of human (-synuclein expression. It was also identified that SNCA-C mice do not have detectable changes to the responsiveness ofDA D2 autoreceptors that regulate DA release. However, DA release in SNCA-C mice was more responsive than Snca -j- controls to the vesicle mobilising properties of cocaine, which suggests altered vesicle mobilisation as a possible mode of action for (-synuclein overexpression. No changes to 5-HT release, explored in substantia, nigra, were observed in SNCA-C mice suggesting that the deficit in neurotransmission does not apply to all monoamines. Rats that express the G2019S or R1441C mutant forms ofLRRK2 revealed an agedependent deficit of evoked DA release in the dorsal striatum, but not the ventral striatum. This deficit in DA release was not accompanied by changes to striatal DA content or the rate of DA uptake, which suggests a change in DA releasability. Taken together, these data suggest that PD related forms of SNCA and LRRK2 cause changes to DA function by affecting DA releasability from axons. Findings presented here are in agreement with other literature to suggest changes in DA synapse function as one of the earliest stages of PD pathophysiology, and may contribute to a deeper understanding of the molecular mechanisms involved in PD. |
