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Nasseri, Glory

University of British Columbia

The formation and remodeling of specialized junctions between neurons, called synapses, requires precise distribution and trafficking of proteins to specialized compartments. Synapse plasticity refers to the continual changes in the strength and structure of these synaptic contacts that occur in response to neuronal activity. This is in large part mediated by post-translational modifications of synaptic proteins, including reversible protein palmitoylation, resulting in the strengthening and weakening of synaptic connections that underlies the cellular basis of learning and memory. To understand how the dynamic palmitoylation of neuronal proteins contributes to synaptic plasticity, we used an unbiased, proteomic approach to identify proteins that were differentially palmitoylated following a hippocampal-dependent fear conditioning learning paradigm in mice. In this study, we identified 121 hippocampal proteins, including several key synaptic proteins, whose palmitoylation status was altered 1 hour after contextual fear conditioning. A subset of the 121 differentially palmitoylated proteins was validated in vitro and the effects of dynamic palmitoylation on the function of a validated protein, lipid phosphate phosphatase-related protein 4 (LPPR4 – also referred to as plasticity-related gene 1, PRG-1), was investigated further. We demonstrate that PRG-1 palmitoylation is regulated by changes in neuronal activity associated with hippocampal learning as well as with chemical long-term potentiation (cLTP). We identified cysteine residues in PRG-1 that are palmitoylated and found that palmitoylation at these sites is important for dendritic spine formation. Furthermore, we demonstrate that increased palmitoylation of PRG-1 negatively regulates bioactive lipid uptake in dendritic spines and shafts and is important for activity-induced insertion of AMPA receptors into the postsynaptic membrane which is essential for synaptic strengthening. As palmitoylation iv can facilitate interactions between proteins and cellular membranes, we tested the hypothesis that neuronal activity modulates membrane surface levels of PRG-1 through palmitoylation. However, we discovered that activity-induced palmitoylation of PRG-1 had no effect on its surface expression and therefore likely functions through an alternative mechanism. These findings suggest that dynamic palmitoylation of PRG-1 contributes to hippocampal synapse plasticity by modulating bioactive lipid uptake, spine formation, and activity-induced AMPA receptor recruitment. Together, this study identifies dynamic palmitoylation networks which may be central to learning and memory.

Text

2022-07-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79411

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/