The role of DHHC5-mediated palmitoylation of delta-catenin in cadherin stability and synapse plasticity

Synapses of the Central Nervous System are specialized junctions of cell-cell contact that transmit signals from one neuron to another in a rapid and efficient manner. Synapses are highly plastic structures that can be continually modified in response to fluctuations in neuronal activity. Changes in the number, size, and protein composition of synapses have been observed following alterations in neuronal activity in vitro and following the learning of specific tasks in vivo. Thus, elucidating the molecular mechanisms underlying activity-mediated trafficking of proteins to and from synaptic compartments is essential for our understanding of brain function. Previous work has demonstrated a requirement for the cadherin-adhesion complex in activity-induced enhancements in synapse strength, however the molecular mechanisms that translate synaptic activation into enhanced cadherin-based adhesion and synapse strengthening remain unknown. This dissertation discusses work that unravels how synaptic activity coordinates the enhancement of cadherin surface stabilization, enlargement of dendritic spines, and increased surface insertion of AMPA receptors. This work demonstrates that increased synaptic activity enhances the palmitoylation of a brain-specific component of the cadherin-adhesion complex, δ-catenin, which in turn causes δ-catenin to traffic toward the synaptic membrane in spines where it associates with and stabilizes surface N-cadherin. This results in enhancements in synapse structure and efficacy, and is correlated with the acquisition of contextual fear memories. Furthermore, we show that palmitoylation of δ-catenin is mediated by the palmitoyl acyl-transferase DHHC5, and that DHHC5 drives activity-induced increases in surface AMPA receptor levels through the palmitoylation of δ-catenin. Finally, we demonstrate that the activity-induced palmitoylation of δ-catenin by DHHC5 is accomplished through the rapid trafficking of DHHC5 out of the synapse and into the dendritic shaft where it can associate with and palmitoylate δ-catenin, resulting in δ-catenin’s synaptic recruitment. This work provides new insights into the cellular and molecular mechanisms that underlie activity-induced synapse plasticity.Medicine, Faculty ofGraduat