Chronic reduction of synaptic proteins in the epileptogenic lesion of patients with hippocampal sclerosis

Akiko Oota-Ishigaki¹Nami Suzuki¹Keiya Iijima²Yutaro Takayama²Yuiko Kimura²Kotaro Hattori²Masaki Iwasaki²Takashi Hayashi^1*

• ¹National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
• ²National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan

Disturbance of synaptic proteins in the epileptogenic lesion are considered the basis for drug-resistant focal epilepsy. However, details of these molecular changes remain unknown because brain tissues are typically uncollectable from living patients. Using surgically excised brain tissues from epileptogenic lesions of patients with hippocampal sclerosis, we biochemically studied quantitative alterations in synaptic protein expression and their post-translational phosphorylation of synaptic proteins including glutamate receptors, the major excitatory neurotransmitter receptors. Compared to less epileptogenic control regions, most patients showed reduced synaptic protein expression in the lesion and decreased α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor phosphorylation in the epileptogenic lesion, indicating an overall weakening of synapses in the chronic condition. These molecular disturbances may explain clinically observed basal hypoactivity and hypometabolism in epileptogenic lesions and may function as a fundamental mechanism of epileptogenesis. Furthermore, a history of febrile seizures was associated with increased AMPA receptor phosphorylation, which correlates with the enhancement of excitatory synaptic strength and reduced thresholds of hyperexcitation.