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Regulation of cadherin adhesion complexes and their modulators : effects on synapse formation and plasticity Globa, Andrea Kathleen

Abstract

Synapses of the central nervous system are specialized points of cell-cell contact that transmit signals from one neuron to another in an efficient manner. A fundamental property of synapses is that they can be altered in response to activity, a process called “synaptic plasticity.” Synaptic activity can cause lasting increases in synaptic strength (long-term potentiation, or ‘LTP’), and decreases in synapse strength (long-term depression, or ‘LTD’). The cell adhesion molecules ‘cadherins’ and their intracellular binding partners β-catenin and δ-catenin are key mediators of synaptic plasticity. The disruption of the cadherin adhesion complex impairs LTP, and increased cadherin stability at synaptic membranes impairs LTD. The role of cadherins in synaptic plasticity has been well studied in the hippocampus, and cadherins have been shown to influence spatial learning and memory. However, little is known about the importance of cadherins in other brain regions, and in other forms of learning. In the first half of this dissertation, I examine the role of the cadherin adhesion complex in cocaine-mediated plasticity in the ventral tegmental area (VTA) of the mesocorticolimbic dopamine circuit. I demonstrate that cadherins play an important role in activity- and cocaine-mediated plasticity in the VTA. Furthermore I find that increasing cadherin localization at the synaptic membranes of VTA dopamine cells impairs AMPA receptor trafficking, synaptic plasticity, and cocaine-mediated behavioural conditioning. Previous work has also shown that the cadherin adhesion complex protein, δ-catenin, can be modified through the addition of the fatty acid, palmitate, to cysteine residues in a process called palmitoylation. δ-catenin palmitoylation results in increased cadherin-δ-catenin interactions and increases in synapse strength. The palmitoylation of δ-catenin is mediated by the palmitoyl acyltransferase, zDHHC5. Although zDHHC5 has been shown to play an important role in synaptic plasticity, its role in neuronal development has not been examined. In the second half of this dissertation, I examine the role of zDHHC5 in dendrite outgrowth and synapse formation, finding that the palmitoylation function and proper localization of zDHHC5 at the plasma membrane of postsynaptic spines are important for the stability of dendritic spines and the formation of excitatory synapses.

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