Temporal and protein-specific S-palmitoylation supports synaptic and neural network plasticity

Abstract

S-palmitoylation, a dynamic post-translational modification, has long been suggested to play a pivotal role in synaptic plasticity, learning, and memory. However, its precise impact on synaptic proteins and function remains unclear. In this study, we show that acute protein depalmitoylation in the hippocampus differentially affects short- and long-term synaptic plasticity, depending on synapse type. Strikingly, depalmitoylation also reprograms neuronal spiking timing following associative network activation. Our research identifies pre- and postsynaptic proteins dynamically regulated by S-palmitoylation during synaptic plasticity and suggests this modification occurs in isolated excitatory synapses. We also demonstrate that S-palmitoylation targets specific proteins within minutes and is not proteome-wide. These findings mark a significant advance in understanding how lipid modifications drive neural adaptability, memory, and learning.