Abstract
AMPA receptors are responsible for fast excitatory synaptic transmission in the mammalian brain. Post-translational protein S-palmitoylation of AMPA receptor subunits GluA1-4 reversibly regulates synaptic AMPA receptor expression, resulting in long-lasting changes in excitatory synaptic strengths. Our previous studies have shown that GluA1 C-terminal palmitoylation-deficient (GluA1C811S) mice exhibited hyperexcitability in the cerebrum and elevated seizure susceptibility without affecting brain structure or basal synaptic transmission. Moreover, some inhibitory GABAergic synapses-targeting anticonvulsants, such as valproic acid, phenobarbital, and diazepam, had less effect on these AMPA receptor palmitoylation-deficient mutant mice. This work explores pharmacological effect of voltage-gated ion channel-targeted anticonvulsants, phenytoin and trimethadione, on GluA1C811S mice. Similar to GABAergic synapses-targeting anticonvulsants, anticonvulsive effects were also reduced for both sodium channel- and calcium channel-blocking anticonvulsants, which suppress excess excitation. These data strongly suggest that the GluA1C811S mice generally underlie the excessive excitability in response to seizure-inducing stimulation. AMPA receptor palmitoylation site could be a novel target to develop unprecedented type of anticonvulsants and GluA1C811S mice are suitable as a model animal for broadly evaluating pharmacological effectiveness of antiepileptic drugs.
Highlights
Various anticonvulsants are clinically used in the treatment of epileptic seizures (Beck and Elger, 2008; Goldenberg, 2010)
More than a hundred genes have been identified as causative genes for epilepsy to date and a lot of epilepsy-related mutations locate on loci coding ion channels (Helbig and Ellis, 2020)
In addition to our previous verification using AMPA receptor palmitoylation-deficient (GluA1C811S) mice with GABAergic synapses-targeting anticonvulsants, we further showed in this report that reduced anticonvulsive effects are observed when GluA1C811S mice are treated by voltage-gated ion channelblocking anticonvulsants, PHT (Figure 1) and TMZ (Figure 2)
Summary
Various anticonvulsants are clinically used in the treatment of epileptic seizures (Beck and Elger, 2008; Goldenberg, 2010). Antiepileptic drugs (AEDs) affect several pharmacological targets to suppress excessive neuronal firing, resulting in prevention of the seizure spread in the brain. Disrupted excitatory/inhibitory (E/I) balance results in perturbed brain function and repetitive seizures leads to serious epilepsy (Paz and Huguenard, 2015). Over the past few decades, many seizure models in rodents have been established for the pharmacological testing of epileptic modifiers (Guillemain et al, 2012; Löscher, 2016; Löscher, 2017). Symptom-mimicking behavioral outcomes in these models provide an indicator of pharmacological effects on epileptic seizure. In addition to acute seizure models using drugs and chemically or electrically
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