Temporal lobe epilepsy is the most common form of epilepsy in adults. Currently available anti-epileptic drugs often have significant and debilitating side-effects, and temporal lobe epilepsy frequently becomes resistant to drug therapy, presenting an enormous social and medical problem. The central idea behind the proposed research 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 the limbic 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 been demonstrated in the healthy developing hippocampus, and it has been shown that modulation of single hub cells in slices can block the spontaneous bursting activity of the entire network. Here we propose to use novel optogenetic approaches to selectively inhibit abnormal hub-like cells in the dentate gyrus and entorhinal cortex of epileptic adult mice in vivo in order to prevent the hyper-activation of the commissural-associational and temporo-ammonic pathways within the entorhino-hippocampal network specifically at the onset of spontaneous recurrent seizures. Because the manipulation will affect only a few cells in the entire limbic system in a temporally selective manner, effective seizure control may be achieved with minimal effects on the normal information processing of the circuit. If successful, the proposed research will demonstrate a fundamentally novel 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 with existing drug therapies. Spontaneous seizures may be caused by persistently altered circuits that emerge after precipitating insults. The project will determine whether transiently inhibiting pathologically super-connected neurons using cutting-edge optical techniques can prevent the generation of seizures. ****Please note that reviewers were given the following special instructions for the review of these Exceptional Unconventional Research Enabling Knowledge Accelerations (EUREKA) grant applications: The purpose of the EUREKA initiative is to foster exceptionally innovative research that, if successful, will have an unusually high impact on the areas of science that are germane to the mission of one or more of the participating NIH institutes. EUREKA is for new projects. EUREKA is not for the continuation of existing projects. EUREKA is not for support of pilot projects (i.e., projects of limited scope that are designed primarily to generate data that will enable the PI to seek other funding opportunities). Rather, it is anticipated that EUREKA projects will begin and be completed during the funding period. Please provide an opinion and assessment of the likelihood the project will exert a sustained, powerful influence on the research field(s) involved. Significance and innovation should be the major determinants of your overall impact score. The approach should be evaluated for general feasibility. An application should score poorly if it is clear to the reviewers that the proposed methodology has no probability at all of being successful, either because it is inherently illogical or because the same approach has already been attempted and shown not to be feasible. Remember that unavoidable risk, which is intrinsic to novel and innovative approaches, is expected for these applications and reviewers are instructed that the presence or absence of preliminary data should not be taken into account when determining the score. Applications that are good science for standard research type investigation, but not likely to exert a sustained and powerful influence on the field, should be scored down.
| Bui, Anh D; Nguyen, Theresa M; Limouse, Charles et al. (2018) Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory. Science 359:787-790 |
| Bui, Anh D; Alexander, Allyson; Soltesz, Ivan (2017) Seizing Control: From Current Treatments to Optogenetic Interventions in Epilepsy. Neuroscientist 23:68-81 |
| Krook-Magnuson, Esther; Soltesz, Ivan (2015) Beyond the hammer and the scalpel: selective circuit control for the epilepsies. Nat Neurosci 18:331-8 |
| Bui, Anh; Kim, Hannah K; Maroso, Mattia et al. (2015) Microcircuits in Epilepsy: Heterogeneity and Hub Cells in Network Synchronization. Cold Spring Harb Perspect Med 5: |
| Armstrong, Caren; Krook-Magnuson, Esther; Oijala, Mikko et al. (2013) Closed-loop optogenetic intervention in mice. Nat Protoc 8:1475-1493 |
| Krook-Magnuson, Esther; Armstrong, Caren; Oijala, Mikko et al. (2013) On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat Commun 4:1376 |
| Krook-Magnuson, Esther; Varga, Csaba; Lee, Sang-Hun et al. (2012) New dimensions of interneuronal specialization unmasked by principal cell heterogeneity. Trends Neurosci 35:175-84 |
| Soltesz, Ivan (2011) The Brain Prize 2011: From Microcircuit Organization to Constellations of Brain Rhythms. Trends Neurosci 34:501-3 |
