LAUSR

In the mammalian CNS, glutamate is the major excitatory neurotransmitter. Ionotropic glutamate receptors (iGluRs) are responsible for the glutamate‐mediated postsynaptic excitation of neurons. Regulation of glutamatergic synapses is critical for higher brain functions including neural communication, memory formation, learning, emotion, and behaviour. Many previous studies have shown that post‐translational protein S‐palmitoylation, the only reversible covalent attachment of lipid to protein, regulates synaptic expression, intracellular localization, and membrane trafficking of iGluRs and their scaffolding proteins in neurons. This modification mechanism is extremely conserved in the vertebrate lineages. The failure of appropriate palmitoylation‐dependent regulation of iGluRs leads to hyperexcitability that reduces the maintenance of network stability, resulting in brain disorders, such as epileptic seizures. This review summarizes advances in the study of palmitoylation of iGluRs, especially AMPA receptors and NMDA receptors, and describes the current understanding of palmitoylation‐dependent regulation of excitatory glutamatergic synapses.