TY - JOUR T1 - Tonic Inhibition is Abolished in GABA<sub>A</sub> Receptor γ2R43Q Knock-in Mice with Absence Epilepsy and Febrile Seizures JF - bioRxiv DO - 10.1101/155556 SP - 155556 AU - Kile P. Mangan AU - Wyatt B. Potter AU - Aaron B. Nelson AU - Steve Petrou AU - Stephen M. Johnson AU - Avtar Roopra AU - Chiara Cirelli AU - Mathew V. Jones Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/26/155556.abstract N2 - The γ2R43Q GABAA receptor mutation confers absence epilepsy in humans, and γ2R43Q knock-in mice (RQ) display absence seizures and generalized spike-and-wave discharges reminiscent of their human counterparts. Previous work on several rodent models led to the conclusion that elevated tonic inhibition in thalamic neurons is necessary and sufficient to produce typical absence epilepsy. In contrast, here we used patch-clamp electrophysiology in brain slices to show that RQ mice entirely lack tonic inhibition in principal cells of layer II/III somatosensory cortex and ventrobasal thalamus. Additionally, protein quantification and multielectrode electrophysiology show that the mutation interferes with trafficking of GABAA receptor subunits involved in generating tonic currents, leading to increased cortical firing and decreased thalamic bursting rates. Together with previous work, our results suggest that an optimum level of tonic inhibition is required for normal thalamocortical function, such that deviations in either direction away from this optimum enhance susceptibility to absence seizures. ER -