Investigating the Effect of Vesicular Acetylcholine Transporter Expression on Central and Peripheral Function

Résumé du livre

Cholinergic neurons use the neurotransmitter acetylcholine extensively throughout the central and peripheral nervous systems. During normal and pathological aging (i.e. Alzheimer's disease) cholinergic neurotransmission decreases, particularly in the basal forebrain which supplies the cortex and hippocampus with cholinergic input. This thesis investigates the effect of vesicular acetylcholine transporter (VAChT) overexpression on cholinergic function. The biochemical characteristics of cholinergic neurons following VAChT overexpression were measured and the behaviour phenotype of these animals was evaluated. Furthermore, the effect of lifelong VAChT overexpression on the age-related impairment of hippocampal structure and function was determined. No overt differences in the expression levels of presynaptic cholinergic transcripts and proteins were observed following VAChT overexpression in mice. With this absence of presynaptic compensation, acetylcholine release in the hippocampus was found to be significantly elevated. While this increased level of acetylcholine release was not sufficient to significantly modify peripheral function, we observed behavioural phenotypes conducive to central cholinergic action. VAChT overexpressing mice exhibited decreased locomotion and enhanced response to novelty in the open field. In addition, these mice displayed a release of exploratory inhibition. These data support the ability of VAChT to modulate cholinergic tone and central cholinergic function. Using a model of normal aging, VAChT overexpression was found to enhance dendritic ramification in newborn neurons of the hippocampus. An improvement of the precision of spatial memory acquisition was also observed in aged mice overexpressing VAChT. These data provide direct immunohistological evidence that VAChT overexpression augments dendritic expansion in the hippocampus and that VAChT contributes to improved precision of hippocampal-dependant spatial memory. In conclusion, this thesis demonstrates that VAChT overexpression augments central cholinergic function related to locomotion, response to novelty and hippocampal structure and that these features may in part contribute to superior spatial memory during aging.