Dynamic regulation of palmitoyltransferases by synaptic activity
The formation and remodeling of synaptic contacts require the precise distribution and trafficking of proteins to specialized compartments. This dynamic trafficking of synaptic proteins is partly controlled by S-palmitoylation, which is the most common form of post-translational lipid modification in the brain. Notably, several studies have shown that synaptic proteins can be differentially palmitoylated in response to synaptic activity. However, it is unclear how changes in synaptic activity alters protein palmitoylation. Here we show that increasing synaptic activity in primary rat hippocampal cultures using a well-established chemical LTP (cLTP) paradigm leads to post-translational modifications in ZDHHC enzymes which in turn impact enzyme stability, protein interaction and function. Notably, we observe the same post-translational modifications following the acquisition of contextual fear memory in vivo. In contrast to that observed for palmitoylating enzymes, we observed no activity-induced changes in the activity of thioesterases nor post-translational modifications of the thioesterase, ABHD17. These findings suggest that the differential palmitoylation of synaptic proteins following synaptic stimulation is mediated through post-translational modifications of ZDHHC enzymes that in turn regulate enzyme stability and function, and not through changes in depalmitoylating thioesterases.