Epigenetic Regulation Of Tonic Inhibition In Epilepsy

Epilepsy can be either acquired or genetic. In both cases, seizures can trigger long-term changes such as an imbalance between neuronal excitation and inhibition. Inhibition comes in two major flavors, both mediated by the neurotransmitter GABA acting through GABAA receptors: a) fast and brief synaptic transmission and b) constant activation of receptors by low ambient concentrations of GABA (i.e., “tonic inhibition”). A growing wealth of evidence shows that increases or decreases in tonic inhibition are associated with epilepsy; however, what controls the levels of genes important for tonic inhibition is unknown. All genes are controlled by transcription factors (TFs). Some TFs control thousands of genes and are often called “Master Regulators”. Dr. Roopra’s data suggests that a Master Regulator called Polycomb (Pc) is induced in multiple epilepsy models and suppresses a GABAA receptor gene called delta that is normally required for tonic inhibition. Importantly, there are drugs already in clinical trials for other diseases that could be re-purposed to suppress Pc and restore GABA-delta expression and thus restore healthy levels of tonic inhibition.