AMPA receptor palmitoylation restrains ictogenesis in the epileptogenic lesion of patients with hippocampal sclerosis

Failure of appropriate synaptic regulation in the epileptogeniclesion leads to sudden onset ictogenesis in severe epileptic seizure. Using surgically excised patient brain tissue, our recent biochemical study revealed chronic reduction of synaptic protein expressions in the epileptogenic lesions of patients with hippocampal sclerosis. α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors are the major excitatory neurotransmitter receptors in human brain. Decreased AMPA receptors expression and their phosphorylations in the epileptogenic lesion induce an overall reduction of excitatory synaptic functions in the chronic condition. These molecular disturbances could be fundamental mechanisms underlying clinically observed basal hypoactivity and hypometabolism in epileptogenic lesions, which are characteristic of epileptogenesis. Here, we further report that AMPA receptor palmitoylation, another reversible post-translational protein modification, is significantly reduced in epileptogenic lesions. In our earlier studies using animal models, the chemically induced-seizure threshold was significantly lower in AMPA receptor palmitoylation-deficient mice, compared to wild-type control mice. Decreased AMPA receptor palmitoylation in the epileptogeniclesion of patients indicates an impaired ability to suppress hyperexcitability, potentially contributing to ictogenesis.