With 5-10 cases of epilepsy per 1000 people in the world, and temporal lobe epilepsy making up over 66% of these cases, temporal lobe epilepsy is considered one of the most prevalent and serious neurological disorders. The annual economic burden of over $12.5 billion in the US alone adds to the considerable cost in the quality of life of epileptic patients, and calls for efforts to better understand the mechanisms underlying spontaneous seizures. A neuronal cell population that may play a key role in seizure activity is hippocampal mossy cells, which are critically important in the dentate gyrus excitatory network. This project proposes to test the hypothesis that mossy cells are central to amplifying and propagating hyperexcitable activity, and contribute to the development of debilitating epilepsy-related cognitive deficits. The hypothesis will be tested during the chronic epilepsy period of the intrahippocampal kainate epilepsy model. Alterations occurring in the dentate gyrus of the mouse hippocampus will be investigated using a combination of in vivo electrophysiological and closed-loop optogenetic methods, as well as learning and memory studies. Discerning the role of mossy cells in temporal lobe epilepsy and related cognitive impairments may open doors in the development of novel therapeutical approaches for this disorder.
Altered excitatory network signaling is an important mechanism underlying recurrent, spontaneous seizures. This proposal examines whether mossy cells in chronic temporal lobe epilepsy are responsible for seizure amplification and propagation, and if seizure control by modulating mossy cell activity can ameliorate hippocampal-dependent cognitive impairments associated with chronic epilepsy.
|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|
|Maroso, Mattia; Szabo, Gergely G; Kim, Hannah K et al. (2016) Cannabinoid Control of Learning and Memory through HCN Channels. Neuron 89:1059-73|
|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:|
|Krook-Magnuson, Esther; Armstrong, Caren; Bui, Anh et al. (2015) In vivo evaluation of the dentate gate theory in epilepsy. J Physiol 593:2379-88|
|Reeber, Stacey L; Otis, Tom S; Sillitoe, Roy V (2013) New roles for the cerebellum in health and disease. Front Syst Neurosci 7:83|