Epilepsy is a neurological disorder that affects millions of people worldwide. The condition is characterized by recurrent, unprovoked seizures caused by an imbalance in the brain’s electrical rhythms. However, the mechanisms underlying epileptogenesis, the development of epilepsy, remain unknown. Now, researchers from Yokohama City University in Japan have shed light on the biological basis of epilepsy in humans and explored the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in epileptogenesis.
AMPARs play a vital role in synaptic plasticity, the process by which neuronal activity causes changes in the strength of the connections between neurons. To study the relationship between AMPAR density and dynamic electrical activity in the brain, researchers from Yokohama City University developed a novel radiotracer, [11C]K-2. This radiotracer is the first technology that can quantitatively visualize and measure AMPAR density in the living human brain. The researchers used positron emission tomography (PET) and electroencephalography (EEG) to analyze the role of AMPARs in epileptogenesis.
The team monitored the trafficking of radiolabeled AMPAR in patients with epilepsy. They found that cell surface AMPAR density positively correlated with the amplitude of gamma activity in focal epilepsy. Moreover, the transition from focal to generalized seizures was accompanied by a disappearance of positive AMPAR-theta activity coupling and the spread of negative AMPAR-theta activity coupling. This result is significant as the presence of focal to bilateral tonic-clonic seizure is reportedly the most significant risk factor for sudden unexpected death in epilepsy.
The team also found that, in patients with focal onset seizures, an increase in AMPAR trafficking increased the amplitude of abnormal gamma activity. Patients with generalized onset seizures, however, showed a decrease in AMPAR on the cell surface, which was associated with an increase in the amplitude of abnormal gamma activity. The researchers also noted that patients with epilepsy showed lower AMPAR levels than healthy controls. Patients with generalized onset seizures showed lower AMPAR levels in larger areas of the cortex than patients with focal onset seizures.
“Given these findings, we think that Hebbian plasticity to increase AMPAR trafficking and homeostatic scaling for the compensatory downregulation of synaptic function in seizures could regulate epileptic brain function,” says Prof. Takuya Takahashi, lead author of the study.
The researchers’ findings have laid to rest several doubts about the biological basis of epilepsy in humans and may lead to the development of novel and effective therapeutics for patients suffering from this disorder. Their study has been published in the journal Cell Reports Medicine.
