Optogenetic control of epileptiform activity

Abstract

The optogenetic approach to gain control over neuronal excitability both in vitro and in vivo has emerged as a fascinating scientific tool to explore neuronal networks, but it also opens possibilities for developing novel treatment strategies for neurologic conditions. We have explored whether such an optogenetic approach using the light-driven halorhodopsin chloride pump from Natronomonas pharaonis (NpHR), modified for mammalian CNS expression to hyperpolarize central neurons, may inhibit excessive hyperexcitability and epileptiform activity. We show that a lentiviral vector containing the NpHR gene under the calcium/calmodulin-dependent protein kinase II␣ promoter transduces principal cells of the hippocampus and cortex and hyperpolarizes these cells, preventing generation of action potentials and epileptiform activity during optical stimulation. This study proves a principle, that selective hyperpolarization of principal cortical neurons by NpHR is sufficient to curtail paroxysmal activity in transduced neurons and can inhibit stimulation train-induced bursting in hippocampal organotypic slice cultures, which represents a model tissue of pharmacoresistant epilepsy. This study demonstrates that the optogenetic approach may prove useful for controlling epileptiform activity and opens a future perspective to develop it into a strategy to treat epilepsy.epilepsy ͉ hippocampus ͉ NpHR ͉ paroxysmal depolarizing shift (PDS) ͉ stimulation train-induced bursting (STIB)

Potentiel thérapeutique de la neuromodulation optogénétique

“…Une première stratégie consiste à utiliser des outils optogénétiques hyperpolarisants pour inhiber directement les cellules excitatrices dont l'hyperactivité est responsable de l'apparition et de la propagation de l'activité ictale ( Figure 4A). Dès 2009, une première étude a démontré que l'expression ciblée de l'halorhodopsine de l'archée Natronomonas pharaonis (NpHR) pouvait être utilisée pour réduire ou inhiber des bouffées d'activité épileptiforme induites par stimulation électrique dans des cultures organotypiques d'hippocampe [44]. Cette approche a par la suite été validée in vivo dans différents modèles murins, obtenus par injection de substances épileptogènes.…”

Optogenetics in neuroscience: what we gain from studies in mammals

“…and epileptiform activity of hippocampal CA3 neurons by activating NpHR [49] . They provided a novel preliminary direction for the optogenetic treatment of epilepsy.…”

Shining Light on Epilepsy: Optical Approaches for Treating Seizures

“…In the field of neuroscience, light-sensitive channel proteins that depolarize or hyperpolarize neurons are among the most useful. In particular, genetic transfection of light-sensitive halorhodopsin chloride pumps into mice allows light-activated hyperpolarization of hippocampal neurons and suppression of epileptiform activity in hippocampal slice cultures (8). Very recent, innovative studies demonstrate the ability of optogenetic methods to inhibit behavioral seizures in rats in vivo (9-11; also the subject of a future Epilepsy Currents article).…”