Towards therapies for epilepsy: Probing the potential of NMDA receptor allosteric modulation.

Epilepsy is one of the most debilitating brain disorders and to date there is a shortage of drugs to combat it effectively. This is in part the result of the complexity of epileptic seizures, which arise from interactions amongst diverse excitatory and inhibitory neurons expressing numerous ion channels and receptors as well as relevant models. Here we propose to establish two in vitro models of seizure activity, based on mouse hippocampal brain slices and neurons derived from human induced pluripotent stem cells, to investigate the efficacy of novel modulators at one key brain receptor - the glutamatergic NMDA receptor – in controlling seizure activity. In this pilot project we will investigate both positive and negative allosteric NMDA receptor modulators using a combination of electrophysiological techniques including field potential recordings, multi-neuron patch-clamp electrophysiology and multi-electrode array recordings to understand the locus of action of these drugs at the excitatory and inhibitory neurons of the brain and their ability to control seizure activity. This will allow a deeper appreciation of the balance of excitation and inhibition in the generation of seizure activity, reveal the potential of allosteric modulation in controlling seizures and provide the preliminary data for future grant applications to study their effect in vivo.

Keywords:STEM CELL PHYSIOLOGY, HIPPOCAMPUS, EPILEPSY MODEL, EPILEPSY

Disciplines:Neurological and neuromuscular diseases, Neurophysiology, Electrophysiology