The majority of excitatory synapses in the central nervous systems are found on small actin-rich protrusions known as dendritic spines containing a postsynaptic membrane specialization called the postsynaptic density (PSD). These structures are remarkably dynamic, with both postsynaptic glutamate receptors and PSD structural molecules being trafficked rapidly in and out of spines to regulate dendritic spine structure and synaptic strength. In particular, this dynamic control of postsynaptic structure and protein composition is essential for controlling forms of synaptic plasticity that underlie learning and memory, such as long-term potentiation (LTP) and long-term depression (LTD). Two key regulators of postsynaptic structure and function are adhesion and scaffolding molecules. N-cadherin (N-cad) is an adhesion molecule that links the pre- and postsynapse and modulates excitatory transmission. Importantly, postsynaptic N-cad recruitment and stabilization is required for LTP, but the mechanisms of N-cad trafficking to and from synapses remain largely unexplored. Recycling endosome (RE) exocytosis is an important pathway for trafficking cargo to the dendritic plasma membrane in support of dendritic spine growth and synaptic potentiation. RE exocytosis may provide a link between structural and functional plasticity by delivering membrane, glutamate receptors, and other postsynaptic molecules that are required to sustain synaptic potentiation and spine enlargement during LTP. Lipid modifications, such as palmitoylation, are important for protein localization, including targeting to the synaptic membrane and REs. Palmitoylation is a reversible lipidation of cysteine residues that is emerging as an important regulator of synaptic plasticity through its ability to control trafficking and function of a number of postsynaptic proteins. A-Kinase Anchoring Protein 79/150 (AKAP79/150, human/rodent) is a postsynaptic scaffolding protein that interacts with N-cad through its N-terminal membrane targeting domain and anchors kinases (PKA, PKC) and phosphatases (Calcineurin/PP2B). AKAP79/150 is palmitoylated and when this lipid modification is prevented, AKAP79/150 localization to dendritic REs is lost, activity-induced RE exocytosis is impaired, and delivery of the AKAP and AMPARs to synapses during LTP is prevented. Here I propose to test the hypothesis that AKAP79/150 palmitoylation regulates N-cad trafficking and stabilization at synapses and in synaptic plasticity through two aims. I will examine the role of AKAP palmitoylation in N-cad synaptic localization (Aim 1) and synaptic plasticity (Aim 2).
Connections between nerve cells in the brain, called synapses, are modulated during learning and memory and dysfunction in synaptic connections during synaptic plasticity is implicated in numerous neurological and neuropsychiatric disorders. Two proteins that regulate the synaptic connections are AKAP79/150 and N- cadherin, which interact and are regulated in the learning and memory process. Here I propose to test the hypothesis that AKAP79/150 is required for proper N-cadherin synaptic localization and synaptic plasticity.
| Purkey, Alicia M; Woolfrey, Kevin M; Crosby, Kevin C et al. (2018) AKAP150 Palmitoylation Regulates Synaptic Incorporation of Ca2+-Permeable AMPA Receptors to Control LTP. Cell Rep 25:974-987.e4 |
