Epilepsy Drug Target May Have Implications for Brain Disorder Sleep Disruption

 

April 2014 — The enzyme GABA transaminase, which is the target of some epilepsy drugs, contributes to sleep loss in fruit flies, a recent study from the University of Pennsylvania has found.

Published online in Molecular Psychiatry, the study looked at the proteomics of the mutant fruitfly called sleepless (sss) brain—a large-scale study of the structure and function of related proteins—and found that GABA transaminase is increased in the sss brain compared to controls. This enzyme breaks down GABA, so GABA is decreased in the sss brain. Because GABA promotes sleep, there is a decrease in sleep in the sss mutant fly.

Researchers say relationship between the SSS protein and GABA is not fully understood. The SSS protein controls neural activity, and its absence results in increased neural firing, which likely uses up a lot of energy. GABA transaminase works in the mitochondria, the energy- production organelle in the glial cells of the brain, which provide fuel for neurons. The large energy demand created by the increased neural firing in sss brains probably alters mitochondrial metabolism, including GABA transaminase function in glia.

In the sss mutant fly, there is a stream of connections that leads to its signature loss of sleep: The sssmutant has increased neuron firing caused by downregulation of a potassium channel protein called Shaker. Recently, the researchers of the study showed that SSS also affects activity of acetylcholine receptors. Both of these actions may directly cause an inability to sleep.

In addition, increased energy demands on glia, which increase GABA transaminase and decrease GABA, may further contribute to sleep loss. However, if GABA is increased, then sleep is increased, as in flies that lack GABA transaminase.

 

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