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GABA mediated vulnerable developmental periods: a potential target for diseases such as epilepsy and autism

Proper excitation-inhibition balance is crucial for normal brain function and particularly during critical periods of development, when neurons are still immature and brain circuits not yet fully formed. 

For example increases in neuronal excitability through inactivation of Kv7 voltage gated K+ channel current results in epilepsy in mice. A recent study by Marguet et al. showed that restoring excitation-inhibition balance in these mice during a critical window (first two weeks of life) prevents later development of epilepsy. The authors used Bumetanide, an FDA approved NKCC1 antagonist (cation-chloride cotransporter) to reduce intracellular chloride concentration and thereby reduce excitatory action of GABA in immature neurons. Notably, treatment during the critical window with Bumetanide was able to normalize network activity and prevent later epileptogenesis before the onset of symptoms in these mice. 

GABA mediated hyper-excitability in immature brain circuits has also been identified in autism models. In 2014, Tyzio and colleagues showed that maternal treatment with the same drug, Bumetanide, restored electrophysiological and behavioral phenotypes in rodent models of autism (Valproate and Fragile X). 

Translation of these findings to humans is undoubtedly very difficult. A first step are ongoing studies investigating the effect of Bumetanide treatment in individuals with autism and manifest epilepsy. However, preclinical studies investigating the basic underlying mechanisms may help understand the importance of excitation and inhibition of normal network activity and suggest future research avenues to go as far as investigating the potential for disease prevention in some cases. 


Marguet et al. Nature Medicine 2015

Tyzio et al. Science 2014

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