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Parkinson's disease (PD) is a neurodegenerative disorder with no known cure. This thesis explores the degenerative process in two neurotoxin-based models, the 6-hydroxydopamine and the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)/probenecid mouse models, to yield important information about the pathogenesis of PD. Neuronal survival patterns in Parkinsonian patients and animals are heterogeneous. More dopaminergic neurons are lost from the ventral tier of the substantia nigra (SN) than from the dorsal tier or the adjacent ventral tegmental area, possibly due to differential expression of the calcium-binding protein, calbindin D28K. Brain sections were processed for tyrosine hydroxylase (TH) and calbindin (CB) immunocytochemistry to distinguish the dopaminergic subpopulations. I show that more TH+/CB- and TH-/CB+ than TH+/CB+ neurons are lost in both models, suggesting that CB confers some degree of protection for dopaminergic neurons. With respect to connectivity, I show that both TH+ and CB+ neurons receive striatal and dorsal raphe inputs. I investigated the possibility of a progressive loss in midbrain neurons by prolonging the post-lesion survival period. In both models, there is an irreversible neuronal cell loss of TH+, CB+ and TH+/CB+ neurons but the effects of survival time and lesion treatments differ for the three neuronal types. The lesions also appear to be toxic to GABAergic neurons. I explore whether, once neurodegeneration has started, neurons can be rescued by pharmacological intervention. Salicylic acid appears both to reduce microglial activation and significantly improve TH+, but not CB+ or TH+/CB+ neuronal survival. PD appears multifactorial in origin and may involve complex interactions between genetic and environmental influences. I show that a xenobiotic-metabolising enzyme, arylamine N-acetyltransferase may fulfil a neuroprotective role in the SN by limiting the environmental risks. Taken together, this study provides a body of information on two different mouse PD models and highlights possible genetic predispositions to PD neuropathology.

published_or_final_version / Paediatrics / Doctoral / Doctor of Philosophy

published_or_final_version / Anatomy / Master / Master of Philosophy

In deeply anesthetized mammals, as typified by the adult cat, there is limited evidence that the firing-rate response of spinal motor neurons to sustained simulation usually features a progressive reduction in firing rate, termed late adaptation, that begins 1-2 s after the onset of sustained stimulation. The fullest description of late adaptation has been provided by Kernell & Monster (1982a,b) who evoked repetitive firing in spiral motor neurons of deeply anesthetized cats by the conventional procedure of an intracellular injection of a sustained depolarizing current. The main purpose of the present study was to extend on the results of their work. The first hypothesis tested was: Sustained depolarizing extracellular stimulation of motor neurons is more effective in maintaining repetitive discharge than sustained depolarizing intracellular stimulation. Investigations pioneered by Kernell & Monster (1982a,b) tested the association between late adaptation and other type (size)-related properties of motor neurons. Such analyses are within the rubric of Henneman's (1957, 1977) Size Principle, one component of which proposes that the properties of motor neurons and the muscle fibers they innervate are tightly coupled. The second hypothesis was proposed to continue this inquiry. It stated that: Late adaptation (during both sustained and intermittent stimulation), and other discharge-related properties of motor neurons are associated with other type (size)-related properties of these cells and their motor units. For both hypotheses, there was an emphasis on providing a quantitative description of late-adaptation. In the present study, the duration of repetitive firing in response to sustained stimulation significantly exceeded that in the Kernell & Monster (1982a,b) study, thereby providing evidence in support of the first hypothesis. For sustained stimulation, significant associations were found between the time constant of late adaptation and three neuromechanical properties of the cell's motor unit: axonal conduction velocity; twitch contraction time; and, peak tetanic force. Similarly, significant associations were found between the peak firing rate and these neuromechanical properties for both sustained and intermittent stimulation. Significant associations were also found between the extent of between-train adaptation during intermittent stimulation and two of the neuromechanical properties: axonal conduction velocity and peak tetanic force. These results provided evidence in support of the second hypothesis. In summary, the present work has provided a new opening in the study of the active (firing) properties of motor neurons, by quantitating late adaptation during sustained stimulation, and between-train adaptation during intermittent stimulation. This information provides new insights into the fundamental properties of motor neurons and adds important new firing-rate parameters to the continuing evaluation of Henneman's Size Principle.

No description available.

No description available.

No description available.

No description available.