Dissecting Neuronal Participation to Focal Epileptic Events in Vivo
Abstract
Epilepsy is a common severe neurological disorder with high prevalence among military populations. Post-traumatic epilepsy (PTE) is the most common cause of new-onset epilepsy in young adults, with up to 30,000 new cases per year in the United States. The incidence of post-combat PTE is high compared with civilian populations. The Vietnam Head Injury Study, consisting of patients with mostly penetrating head injuries, showed higher than 45% prevalence of PTE. Patients with post-traumatic brain injury carry a high risk of epilepsy for decades following injury. For example, at 15 years following injury, 51% of the subjects in the Vietnam Head Injury Study carried a diagnosis of seizure. Clearly epilepsy is an important problem for Veterans and active military personnel. Currently anti-epileptic drugs fail to achieve adequate seizure control in approximately 30% of all cases. A new approach is needed. Epilepsy is a disorder of neural circuits. Specifically the interaction between different cell types is abnormal and leads to aberrant patterns of activity, which become highly synchronized and manifest as a seizure. One important unresolved question in epilepsy is what particular cell types are involved in the generation and manifestation of seizure events, as well as of other abnormal events recorded in the electro-encephalogram (EEG). For example, it is not well understood what interactions among different cell types cause a seizure to begin or end. Our goal is to understand the contribution of major cell types that participate in the abnormal electrical discharges that cause brain malfunction in focal epilepsy. A failure of specific subsets of neurons, if characterized precisely, will point directly to specific strategies to prevent or reverse the abnormal patterns of activity. To do this, we propose to use state-of-the-art two-photon imaging methods to record in vivo the activity of the multiple identified cortical neurons over months at a time, while monitoring seizure events on cortical surface EEG. Correlating EEG patterns of activity to the signals we extract simultaneously from hundreds of identified cells will allow us for the first time to map how different cell types participate in seizure events in vivo. We will then record from major cell types individually, one cell at a time, under two-photon guidance, to study in detail how each cell type s intracellular potential varies before, during, and after seizure events. We will focus on studying the evolution of abnormal patterns of activity elicited in the cortical microcircuit after inducing an epileptic focus in mouse neocortex by Tetanus Toxin (TeT) injection. TeT injection is a well-validated experimental model of focal epilepsy. It induces an imbalance between excitation and inhibition within the cortical circuit, which reliably leads to the development of chronic focal epilepsy. Excitation to inhibition imbalance plays an important role in post-traumatic epilepsy, as well as in a host of other focal epilepsy models, underscoring the relevance of this model to human disease. What we propose is an essential starting point for gathering the information that will allow us to construct a model of putative cell interactions that lead to seizure events in focal epilepsy. Understanding which interneuron types contribute to the development of hyper-synchrony in focal epilepsy will allow us to design pharmacologic interventions that target specific cell types in the future. This is essential for devising new strategies to "rebalance" cortical activity patterns, restoring normal circuit function. Our proposal represents an important shift of paradigm that is complementary to current not-cell-specific pharmacologic approaches. In summary, we will pioneer a principled and systematic approach for dissecting, in vivo, the mechanisms of focal epilepsy. This approach will usher a new era of single-cell-resolved circuit analysis in epilepsy. Epilep
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510631
Entities
People
- Stelios Smirnakis
Organizations
- Baylor College of Medicine
- United States Army