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 IIalpha 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.