The neurotransmitter GABA is the major inhibitory transmitter in the adult brain, and several antiepileptic drugs exert their effect by promoting inhibition of neurons by GABA. In addition, GABA has other critical roles, such as helping young neurons migrate to the right location as the brain develops. As more information about the timing of sequential stages of development is known, it has become clear that in development GABA may have many actions on development in a short temporal window near the time of birth. Marguet and colleagues (2015) took advantage of this short window and tried to change the course of a type of epilepsy by changing the actions of GABA.

Study Summary

Marguet and colleagues (2015), used a mouse with a mutation in a type of potassium channel, Kv7. These mice developed epilepsy normally, but when the mice were treated in the first two weeks of life, a critical time for development for GABA, the mice with the Kv7 mutation showed dramatic improvement.


The authors not only showed that treatment for just two weeks had a major effect, but they also showed that a drug which antagonizes the actions of GABA worked very well. This drug, bumetanide, has been previously suggested to help epilepsy (Kahle and Staley 2008) but it had not been tested in this way before.

Bumetanide works by blocking the effects of a transporter of chloride ions called NKCC1. Chloride is a critical element of the actions of GABA on GABAA receptors, because those receptors inhibit or excite neurons depending on the gradient for chloride to either enter or exit neurons. When chloride enters neurons, they are hyperpolarized and further from their threshold to generate action potentials; when chloride exits neurons there is a depolarization and the neuron is closer to threshold.

The authors also showed that control mice could be treated and they were not adversely affected. Thus, GABA contributes to the mechanisms which led to the epilepsy, and only in the mice with the mutation. This is very important to the ultimate goal of preventing neurodevelopmental epilepsy because the risk to normal development is always a concern.



Marguet SL, Le-Schulte VT, Merseburg A, Neu A, Eichler R, Jakovcevski I, Ivanov A, Hanganu-Opatz IL, Bernard C, Morellini F, Isbrandt D. 2015. Treatment during a vulnerable developmental period rescues a genetic epilepsy. Nat Med. 21:1436-44.

Kahle KT, Staley KJ. 2008 The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures. Neurosurg Focus. 25(3):E22.

Authored By: 
Helen Scharfman PhD
Authored Date: 
Reviewed By: 
Joseph I. Sirven MD
Tuesday, March 29, 2016