Deficiency of AMPA receptor-palmitoylation aggravates seizure susceptibility

Synaptic AMPA receptor expression controls the strength of excitatory synaptic transmission and plasticity. An excess of synaptic AMPA receptors leads to epilepsy in response to seizure-inducible stimulation. The appropriate regulation of AMPA receptors plays a crucial role in the maintenance of the excitatory/inhibitory (E/I) synaptic balance; however, the detailed mechanisms underlying epilepsy remain unclear. Our previous studies have revealed that a key modification of AMPA receptor trafficking to and from postsynaptic membranes is the reversible, post-translation S -palmitoylation at the C-termini of receptors. To clarify the role of palmitoylation-dependent regulation of AMPA receptors in vivo , we generated GluA1 palmitoylation-deficient (Cys811 to Ser substitution) knock-in mice. These mutant male mice showed elevated seizure susceptibility and seizure-induced neuronal activity, without impairments in synaptic transmission, gross brain structure, and behavior at the basal level. Disruption of the palmitoylation site was accompanied with up-regulated GluA1 phosphorylation at Ser831 but not at Ser845 in the hippocampus, and increased GluA1 protein expression in the cortex. Furthermore, GluA1 palmitoylation suppressed excessive spine enlargement above a certain size after long-term potentiation. Our findings indicate that an abnormality in GluA1 palmitoylation can lead to hyperexcitability in the cerebrum, which negatively affects the maintenance of network stability, resulting in epileptic seizure. SIGNIFICANCE STATEMENT AMPA receptors predominantly mediate excitatory synaptic transmission. AMPA receptors are regulated in a post-translational palmitoylation-dependent manner in excitatory synapses of the mammalian brain. Reversible palmitoylation dynamically controls synaptic expression and intracellular trafficking of the receptors. Here, we generated GluA1 palmitoylation-deficient knock-in mice to clarify the role of AMPA receptor palmitoylation in vivo . We showed that an abnormality in GluA1 palmitoylation led to hyperexcitability, resulting in epileptic seizure. This is the first identification of a specific palmitoylated protein critical for the seizure-suppressing process. Our data also provide insight into how predicted receptors, such as AMPA receptors, can effectively preserve network stability in the brain. Furthermore, these findings help to define novel key targets for developing anti-epileptic drugs.