Temporal lobe epilepsy is the most common form of epilepsy in adults. Currently available anti-epileptic drugsoften have significant and debilitating side-effects, and temporal lobe epilepsy frequently becomes resistant todrug therapy, presenting an enormous social and medical problem. The central idea behind the proposedresearch is that it may be possible to achieve seizure control by transiently inhibiting, only at critical moments,the activity of a low number of unique neurons that may be primarily responsible to triggering seizures in thelimbic system. Our recent large-scale computational modeling studies have shown that rare, abnormal, super-connected, hub-like neurons may play a key role in seizure initiation. Subsequently, such hub cells have beendemonstrated in the healthy developing hippocampus, and it has been shown that modulation of single hubcells in slices can block the spontaneous bursting activity of the entire network. Here we propose to use noveloptogenetic approaches to selectively inhibit abnormal hub-like cells in the dentate gyrus and entorhinal cortexof epileptic adult mice in vivo in order to prevent the hyper-activation of the commissural-associational andtemporo-ammonic pathways within the entorhino-hippocampal network specifically at the onset of spontaneousrecurrent seizures. Because the manipulation will affect only a few cells in the entire limbic system in atemporally selective manner, effective seizure control may be achieved with minimal effects on the normalinformation processing of the circuit. If successful, the proposed research will demonstrate a fundamentallynovel approach to achieving the goal of ?no seizures, no side-effects? for the treatment of epilepsy.
Many patients with temporal lobe epilepsy have repeated spontaneous seizures that cannot be controlled withexisting drug therapies. Spontaneous seizures may be caused by persistently altered circuits that emerge afterprecipitating insults. The project will determine whether transiently inhibiting pathologically super-connectedneurons using cutting-edge optical techniques can prevent the generation of seizures.
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