The emergence of a novel inhibitory brain receptor at the onset of puberty may explain why more than half of children with epilepsy outgrow their seizures, according to a mouse study at SUNY Downstate Medical Center in New York.
The study, “Pubertal Expression of α4βδ GABAA Receptors Reduces Seizure-Like Discharges in CA1 Hippocampus,” published in Scientific Reports, shows that adult mice lacking the GABAR α4βδ (alpha four beta delta) receptor do not have a decrease in their epileptic episodes at puberty, suggesting that it functions as an anti-convulsant during adolescence.
Epilepsy is a common neurological disorder that affects children twice as often as adults, which is consistent with the findings that about 50 to 60 percent of children with epilepsy eventually enter into remission during adolescence. However, the underlying mechanism for this marked decrease in seizures during adolescence was not known.
Previous studies from the SUNY Downstate Medical Center team had shown that the expression of α4βδ GABARs increases four- to eight-fold in specific brain cells of female mice at the onset of puberty. GABA receptors are the most prevalent source of inhibition in the brain and therefore, the researchers hypothesized that this increase in the α4βδ GABARs could explain why children with epilepsy remit at the onset of puberty.
The researchers examined normal mice, both before and at the onset of puberty, and compared them with mice lacking α4βδ GABAR.
“Seizure-like discharges were three to four-fold greater before puberty and in pubertal mice that lack expression of this receptor,” Sheryl Smith, PhD, professor of physiology and pharmacology at SUNY Downstate, said in a press release.
In fact, where control mice showed a decrease in seizure-like activity after reaching puberty, these decreases were not observed in mice lacking the receptor. The researchers then used an agonist of the GABA receptor, which enhances its activity, to address whether they could prevent seizure-like activity.
“Administration of drugs that selectively enhance inhibition mediated by this receptor further decreased seizure-like activity in this model,” Smith said.
These results show that α4βδ GABARs exert anti-convulsant effects selectively at puberty, when expression of this receptor subtype is increased, and show that possible therapies that function to enhance the expression of this receptor may help children suffering from epilepsy.
“These findings suggest a mechanism for remission of epilepsy in adolescence and also suggest potential new therapies for childhood epilepsy,” Smith said.