Deficiency of AMPAR–Palmitoylation Aggravates Seizure Susceptibility

Abstract

Synaptic AMPAR expression controls the strength of excitatory synaptic transmission and plasticity. An excess of synaptic AMPARs leads to epilepsy in response to seizure-inducible stimulation. The appropriate regulation of AMPARs plays a crucial role in the maintenance of the excitatory/inhibitory synaptic balance; however, the detailed mechanisms underlying epilepsy remain unclear. Our previous studies have revealed that a key modification of AMPAR trafficking to and from postsynaptic membranes is the reversible, posttranslational S-palmitoylation at the C-termini of receptors. To clarify the role of palmitoylation-dependent regulation of AMPARs 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, or behavior at the basal level. Disruption of the palmitoylation site was accompanied by upregulated 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 LTP. 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 seizures.

AMPAR Palmitoylation Tunes Synaptic Strength: Implications for Synaptic Plasticity and Disease

“…These data suggest that CS/CS mice are sensitized to recurrent seizures caused by PTZ administration. Furthermore, PTZ-induced seizures in CS/CS mice were resistant to treatments with multiple antiepileptic drugs that potentiate inhibitory (i.e., GABAergic) neurotransmission, such as valproic acid, phenobarbital, and diazepam (Itoh et al, 2018). Together, the evidence provided by Itoh et al (2018) supports a role for synaptic GluA1 palmitoylation in the dampening of synaptic potentiation (cLTP) that may be important for protection from seizure.…”

“…Still, the mechanism by which cLTP is potentiated in CS/CS mice remains unknown. Itoh et al (2018) note that phosphorylation of GluA1 S831, but not S845, was increased at baseline in CS/CS neurons; a third site, S818, was not examined (Itoh et al, 2018). Generally, phosphory-lation at these sites promotes GluA1 surface expression during LTP (Diering and Huganir, 2018).…”

“…In a recent study, Itoh et al (2018) investigated the effect of GluA1 palmitoylation on AMPAR function at hippocampal synapses in vivo. Specifically, AMPAR-mediated synaptic transmission and plasticity were examined in knock-in mice, in which the C-terminal palmitoylation site of GluA1 (a cysteine at residue 811) was replaced by serine (C811S), thus prohibiting palmitoylation.…”

“…In contrast, chemical LTP (cLTP) induced by 30 min bath application of the NMDAR coagonist glycine and the GABA A receptor antagonist picrotoxin was amplified in CS/CS hippocampal neurons, as suggested by greater increases in the volume of dendritic spines. This suggests that GluA1 C811 palmitoylation restricts synaptic AMPAR insertion to limit the extent of synaptic potentiation during cLTP, which may be important for dampening neural excitability in response to strong stimulation (Itoh et al, 2018).…”

“…While progress has recently been made identifying the PATs that mediate steadystate and activity-dependent palmitoylation of synaptic proteins, including AMPARs (Noritake et al, 2009;Fukata et al, 2013;Brigidi et al, 2015;Tabaczar et al, 2017), less is known about the enzymes that depalmitoylate them. However, a clue might come from the finding by Itoh et al (2018) that the greatest increases in dendritic spine size following cLTP occurred in large spines of CS/CS neurons. This suggests that the role of GluA1 C811 palmitoylation is emphasized at these large synapses.…”