The mechanisms underlying the pathogenesis of epilepsy, a neurological disorder characterized by excessive electrical activity in the brain, are still unknown.
Now, using a new radiotracer, researchers from Japan have been able to provide insight into the role of AMPAR trafficking in epileptogenesis.
Radio tracker is (11C) K-2, the first technology to visualize and quantify α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPAR) propionic acid receptors in the living human brain.
Scientists say their findings could lead to the development of new therapies for epilepsy patients.
Epilepsy — a neurological condition that causes unprovoked recurrent seizures — affects millions of people worldwide. While an imbalance in the brain’s electrical rhythms is thought to be a major factor in the cause of epilepsy, the underlying pathophysiological mechanisms remain elusive.
Now on a lesson published in Cell Reports Medicine, a team from Yokohama City University in Japan has studied brain function in epilepsy patients and elucidated the biological basis of this disorder.
AMPAR’s important role
Using positron emission tomography (PET) and electroencephalography (EEG), the team analyzed the role that AMPAR plays in epileptogenesis.
“AMPAR plays an important role in brain synaptic plasticity. Therefore, we recently developed a PET radio locator, (11C)K-2, which is the first and only technology that can be used to calculate the AMPAR density in a living human brain. This tracer allowed us to investigate the relationship between AMPAR density and dynamic electrical activity in the brain as measured by EEG,” said Takuya Takahashi of Yokohama City University Graduate School of Medicine, lead author of the study.
Nerve synapses facilitate the transmission of information across neurons. However, synaptic malfunction causes a variety of brain disorders, including epilepsy. Synaptic plasticity — a process by which neural activity causes changes in the strength of connections between neurons — exists primarily in two forms: Hebbian plasticity and homeostasis. Hebbian plasticity facilitates the mechanism by which information can be encoded and stored in neurons, while homeostatic plasticity moves neurons back to their original state. The current study is based on the premise that damage to synaptic plasticity involving AMPAR triggers epileptogenesis.
To gain insight into the biological mechanisms of epileptogenesis, the researchers monitored trafficking of radioactively labeled AMPARs in epilepsy patients. They saw a positive correlation between the cell surface AMPAR density and the amplitude of gamma activity in focal epilepsy. Also, the transition from focal to generalized seizures is accompanied by loss of coupling positive AMPAR-theta activity and spread of coupling negative AMPAR-theta activity. The investigators say this is particularly important, given that the presence of focal to bilateral tonic-clonic seizures has been reported to be the most significant risk factor for sudden unexpected death in epilepsy.
Abnormal gamma activity
The investigators also found that in patients with focal onset seizures, increased AMPAR trafficking also increased the amplitude of abnormal gamma activity, as seen from EEG measurements. In contrast, patients with generalized onset seizures show decreased AMPAR on the cell surface. This decrease was associated with an increase in the amplitude of the abnormal gamma activity. The researchers also noted that epilepsy patients showed lower levels of AMPAR than healthy controls. Patients with generalized onset seizures also showed lower AMPAR levels in a larger area of cortex than patients with focal onset seizures.
“Given these findings, we think that Hebbian plasticity for increasing AMPAR trafficking and homeostatic scaling for compensatory downregulation of synaptic function in seizures may regulate epileptic brain function,” said Takahashi.
The team says the results could lead to the development of new and effective therapies for patients suffering from this disorder.
Recently, there was good news for childhood epilepsy patients when UCB’s FINTEPLA (fenfluramine) oral solution was approved in the European Union to treat seizures associated with Lennox-Gastaut syndrome as adjunctive therapy to other anti-epileptic drugs for patients two years of age. . age and older.