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.

Long-lasting fear-related disorders depend on the excessive retention of traumatic fear memory. We previously showed that the palmitoylation-dependent removal of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors prevents hyperexcitation-based epileptic seizures and that AMPA receptor palmitoylation maintains neural network stability. In this study, AMPA receptor subunit GluA1 C-terminal palmitoylation-deficient (GluA1C811S) mice were subjected to comprehensive behavioral battery tests to further examine whether the mutation causes other neuropsychiatric disease-like symptoms. The behavioral analyses revealed that palmitoylation-deficiency in GluA1 is responsible for characteristic prolonged contextual fear memory formation, whereas GluA1C811S mice showed no impairment of anxiety-like behaviors at the basal state. In addition, fear generalization gradually increased in these mutant mice without affecting their cued fear. Furthermore, fear extinction training by repeated exposure of mice to conditioned stimuli had little effect on GluA1C811S mice, which is in line with augmentation of synaptic transmission in pyramidal neurons in the basolateral amygdala. In contrast, locomotion, sociability, depression-related behaviors, and spatial learning and memory were unaffected by the GluA1 non-palmitoylation mutation. These results indicate that impairment of AMPA receptor palmitoylation specifically causes posttraumatic stress disorder (PTSD)-like symptoms.

Synaptic plasticity is vital for learning and memory in the brain. It consists of long-term potentiation (LTP) and long-term depression (LTD). Spike frequency is one of the major components of synaptic plasticity in the brain, a noisy environment. Recently, we mathematically analyzed the frequency-dependent synaptic plasticity (FDP) in vivo and found that LTP is more likely to occur with an increase in the frequency of background synaptic activity. Meanwhile, previous studies suggest statistical fluctuation in the amplitude of background synaptic activity. Little is understood, however, about its contribution to synaptic plasticity. To address this issue, we performed numerical simulations of a calcium-based synapse model. Then, we found attenuation of the tendency to become LTD due to an increase in the fluctuation of background synaptic activity, leading to an enhancement of synaptic weight. Our result suggests that the fluctuation affects synaptic plasticity in the brain.

Synaptic plasticity is vital for learning and memory in the brain. It consists of long-term potentiation (LTP) and long-term depression (LTD). Spike frequency is one of the major components of synaptic plasticity in the brain, a noisy environment. Recently, we mathematically analysed the frequency-dependent synaptic plasticity (FDP) in vivo and found that LTP is more likely to occur with an increase in the frequency of background synaptic activity. Previous studies suggest fluctuation in the amplitude of background synaptic activity. However, little is understood about the relationship between synaptic plasticity and the fluctuation in the background synaptic activity. To address this issue, we performed numerical simulations of a calcium-based synapse model. Then, we found attenuation of the tendency to become LTD due to an increase in the fluctuation of background synaptic activity, leading to an enhancement of synaptic weight. Our result suggests that the fluctuation affect synaptic plasticity in the brain.