Advances in the use of GABAergic interneurons for the treatment of epilepsy

Forebrain GABAergic neurons, the main inhibitory type of neuron in the cortex and hippocampus, represent a highly heterogeneous cell population that has been implicated in the predisposition to epilepsy and the onset of seizure. Earlier attempts to restore inhibition and reduce seizure in animal models of epilepsy have been carried out using embryonic basal forebrain tissue as source of immature GABAergic progenitors in cell-based therapies, with promising results. For therapeutic strategies this approach appears unrealistic, while the use of pluripotent stem cells to obtain immature GABAergic neurons opens new and promising avenues. Research on neural stem cells and pluripotent stem cells has greatly advanced and protocols have been established to efficiently direct progenitor cells to differentiate towards the GABAergic lineage. However, being highly heterogeneous, these neurons are difficult to be fully represented in vitro. Better knowledge on the expressed gene profiles, at single cell level, and the differentiation trajectory of these neurons will consent a more precise monitoring of the differentiation steps. Here we review the current literature about how to obtain and characterize genuine inhibitory neurons, how these can be grafted in animal models (and one day possibly in human) and which diseases could potentially be targeted and the efficiency of therapeutic outcome. The main obstacles that need to be overcome are: a) choice of an appropriate animal model, b) availability of human cells prone to GABA differentiation, c) the full representation of all IN subtypes, their proportions and their physiological activities, d) how to monitor them on the long-term after transplant.