Homeostatic Plasticity in the Mechanism and Treatment of Posttraumatic Epilepsy
Abstract
Post-traumatic epilepsy (PTE) is a disabling neurological disorder that develops in some patients after traumatic brain injury (TBI). Because the mechanism is not well understood, this disease is difficult to control and cannot be prevented at present. About one-third of PTE patients cannot be completely controlled by current antiepileptic drugs. Although we know that epileptic seizures are caused by uncontrolled excessive activity of neural network, TBI initially causes brain damage and loss of brain activity. How this depressed activity turns into excessive activity and epileptic seizures in weeks and years after TBI is poorly understood. Interestingly, this transition in activity is similar to a well-studied brain regulation mechanism called “homeostatic plasticity,” in which neurons respond to activity loss by increasing their sensitivity and interconnection so that a certain set level of activity is maintained. In other words, loss of brain activity after TBI is a driving force that causes excessive compensatory activity and development of PTE. This process may be compared to an infarcted heart, which would beat faster to compensate for its lost cardia function. If this hypothesis is correct, then TBI severity and early activity loss should predict later epilepsy development. More importantly, stimulating brain activity, instead of inhibiting it, would reduce intrinsic excessive brain activity through dampening homeostatic plasticity and control epileptic seizure. Our preliminary data strongly support that homeostatic plasticity may underlie the development of PTE and that PTE may be controlled by enhancing brain activity. The current project will address these critical questions on the mechanism and treatment of PTE. We will use two different animal models that are highly related to PTE in humans, particularly in military personnel: a neocortical undercut that models penetrating brain injury and a controlled cortical impact that models mimic brain contusion. To understand the role of homeostatic plasticity in PTE and identify potential electroencephalograph (EEG) biomarker, we will longitudinally image activities in the same groups of neurons as well as a large cortical area of the same mice repeatedly at different times after TBI and determine if chronic PTE develops from initial loss of activity and if such development is consistent with homeostatic plasticity regulation. Neuronal activity will also be compared with simultaneous EEG recording to detect potential early signs of epilepsy development (Aim 1). To determine the effect of enhancing neuronal activity on controlling PTE, we will use a Food and Drug Administration-approved drug (but used for the treatment of tuberculosis) or an optogenetic stimulation technique to stimulate activity of cortical neurons and use video/wireless EEG monitoring to determine if such activity enhancement will reduce and eliminate chronic epileptic seizures that have already developed after TBI (Aim 2). The success of this project will bring about a new concept on the mechanism of PTE and provide a novel strategy for the treatment of PTE. Particularly, a treatment based on a new concept may bring hope for patients with epilepsy that is refractory to the current antiepileptic treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910543
Entities
People
- Xiaoming Jin
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army