Investigation of Cell Types Responsible for Seizure Generation in a Model of Neurofibromatosis Type 1
Abstract
Neurofibromatosis type 1 (NF1) is a genetic condition with a variety of neurological symptoms, including seizures and epilepsy in 15-20% of patients. Close to half of the patients that have NF1 and epilepsy continue to have seizures despite the use of anti-seizure medications. The mechanism behind the increased risk of seizures in NF1 is unknown. Our laboratory recently demonstrated that a mouse model of NF1 also shows an increased seizure risk. We will use this model to answer questions about why seizures are more likely in NF1 compared to the general population. Seizures are often due to increased excitation in the brain. However, increased excitation has not been demonstrated to occur in the NF1 brain. On the other hand, there is increased inhibition, or blockade of activity, in the NF1 brain. At first glance this may seem counter-intuitive for an increased risk of seizures, which are often thought to be related to increased brain activity. However, in recent years, increased inhibition has been shown to play a role in the generation of seizures. We will investigate whether increased excitation versus inhibition is responsible for the increased seizure risk in NF1. We will attempt to answer this question using a variety of neuroscience techniques. We will employ optogenetic techniques, using light to specifically activate different types of neurons, to determine their role in seizures. We will also determine whether the NF1 mutation restricted to excitatory cells or interneurons contributes to increased seizures in these animals. Finally, we will test various drugs targeting specific aspects of the Ras/PI3K/MEK/mTOR pathway that is in part responsible for the increased inhibition, to see whether they can prevent the increased seizure activity. The projects described here will be truly innovative in that they will be the first preclinical studies investigating the mechanisms of increased risk of seizures in patients with NF1. It is crucial that these mechanisms are determined so that we can develop targeted treatments which both treat seizures more effectively than current options and also avoid many of the adverse effects of conventional anti-seizure medications. The results of this study will have important implications for the 15-20% of NF1 patients with epilepsy, especially those patients who do not respond to current anti-seizure medications. Given that some of the drugs we will be testing are already being used in other clinical conditions, it is feasible the findings from this project could translate to the clinical setting in a relatively timely fashion.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210750
Entities
People
- Aylin Y Reid
Organizations
- United States Army
- University Health Network