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The role of beta-catenin and the cadherin adhesion complex in synaptic plasticity, learning and addiction Mills, Fergil

Abstract

A fundamental property of synapses is their ability to change in response to activity, termed ‘synaptic plasticity’. Synaptic activity can cause long-lasting increases in the strength of synapses (long-term potentiation, or ‘LTP’), as well as decreases in synapse strength (long-term depression or ‘LTD’), both of which are believed to be important for learning and memory. The synaptic adhesion molecules ‘cadherins’ and their intracellular binding partner β-catenin have been identified as key mediators of plasticity at synapses. The cadherin adhesion complex is important for maintaining the strength and stability of synapses, and disruption of cadherin function has been shown to impair long-term potentiation (LTP). However, it remains unclear how increases in cadherin adhesion can affect synaptic function and cognition. This is important in light of studies showing that increases in β-catenin levels and mutations in cadherin adhesion complex proteins are associated with many different neurodegenerative diseases, as well as psychiatric disorders such as drug abuse, raising the possibility that aberrant increases in cadherin adhesion may contribute to cognitive impairments in these disorders. In this dissertation, I examine the effects of increases in cadherin adhesion on different forms of synaptic plasticity in the brain. I demonstrate that increases in β-catenin in the hippocampus can stabilize cadherin at the synaptic membrane and abolish long-term depression (LTD) at synapses, leading to significant impairments in spatial memory flexibility and reversal learning. I also demonstrate a role for cadherin in activity- and drug-induced plasticity in the ventral tegmental area (VTA), a region of the brain important for reward learning which is implicated in addiction, and show that cocaine-mediated conditioned place preference results in redistribution of cadherin and AMPA receptors to excitatory synapses onto dopaminergic neurons in the VTA. Together, these results demonstrate that the β-catenin/cadherin adhesion complex plays an important role in several forms of learning and memory, and that aberrant increases in synaptic adhesion can have a detrimental effect on synaptic plasticity and cognitive function.

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Attribution-NonCommercial-NoDerivs 2.5 Canada

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