Temporal lobe epilepsy (TLE) is the most common epilepsy in adults. TLE is often refractory to current anti- epileptic drugs, and systemic treatments are frequently accompanied by significant negative side effects. However, the cellular and circuit mechanisms underlying TLE are not yet understood, which poses a challenge for the development of novel treatment strategies. Recently, we discovered that closed-loop optogenetic intervention (COI) can significantly curtail on-going electrographic and behavioral seizures in chronic experimental TLE with high spatial, temporal, and cell-type specificity, and that it can be used as a powerful, versatile research tool for hypothesis testing o understand TLE mechanisms. Here we propose to test the hypothesis that COI achieves long-term seizure control, as well as the amelioration of cognitive comorbidities and pathological functional network properties, during both the chronic and latent phases of TLE. The hypothesis will be tested in experimental mouse models of TLE, and the assessment will be carried out with electrophysiological and behavioral techniques as well as large-scale in vivo functional imaging methods in the CA1 region of the mouse hippocampus. It is anticipated that defining the functional consequences of COI in TLE will have a significant impact by advancing our understanding of the role of activity-dependent pathological processes in chronic epilepsy and epileptogenesis, and aid the future development of novel anti-epileptic treatment strategies.
Many patients with temporal lobe epilepsy have repeated spontaneous seizures that cannot be controlled with existing drug therapies. The generation of seizures may be effectively controlled by novel interventions that act through light-sensitized neurons (optogenetics). The project will determine the potential of on-demand optogenetic intervention for long-term seizure control and amelioration of the cognitive deficits in epilepsy.
|Soltesz, Ivan; Losonczy, Attila (2018) CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus. Nat Neurosci 21:484-493|
|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|
|Zaremba, Jeffrey D; Diamantopoulou, Anastasia; Danielson, Nathan B et al. (2017) Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion. Nat Neurosci 20:1612-1623|
|Danielson, Nathan B; Turi, Gergely F; Ladow, Max et al. (2017) In Vivo Imaging of Dentate Gyrus Mossy Cells in Behaving Mice. Neuron 93:552-559.e4|
|Maroso, Mattia; Szabo, Gergely G; Kim, Hannah K et al. (2016) Cannabinoid Control of Learning and Memory through HCN Channels. Neuron 89:1059-73|
|Alexander, A; Maroso, M; Soltesz, I (2016) Organization and control of epileptic circuits in temporal lobe epilepsy. Prog Brain Res 226:127-54|
|Danielson, Nathan B; Zaremba, Jeffrey D; Kaifosh, Patrick et al. (2016) Sublayer-Specific Coding Dynamics during Spatial Navigation and Learning in Hippocampal Area CA1. Neuron 91:652-65|
|Danielson, Nathan B; Kaifosh, Patrick; Zaremba, Jeffrey D et al. (2016) Distinct Contribution of Adult-Born Hippocampal Granule Cells to Context Encoding. Neuron 90:101-12|