ABSTRACT
Inherited epilepsies are early and typically lifelong brain network synchronization disorders inextricably linked to ion channel physiology. The last decade of genetic discovery has considerably swelled the list of voltage-gated ion channels contributing to these once enigmatic, developmentally devastating and sometimes fatal monogenic disorders. In silico sequence conservation and in vitro biophysical analysis of epileptogenic subunit variants, particularly in iPSC-derived cells that are co-isogenic with the patient, provide an unambiguous starting point to define the membrane excitability defect attributed to each mutation. However, voltage-clamp assays are not always directly congruent with disease severity, and the functional impact of each channel mutation on firing properties varies dramatically according to the cell type studied and its connectivity. Disparities in expected genotype–phenotype relationships indicate that kinetic anomalies of whole-cell currents in interneurons are only the first stage in unraveling how channels control neural synchrony in complex brain circuits. Strategies to restore channel function are being actively explored, yet our relative ignorance of membrane current homeostasis and excitability remodeling beyond the pore poses a challenge to the discovery of better symptomatic treatment and lasting cures. From a translational perspective, the central question is whether inherited or acquired channelopathy can be rebalanced within specified brain circuits over a prolonged period without deleterious side effects.
