Temporal lobe epilepsy (TLE) is a severe form of epilepsy that typically develops in adults that experience a brain injury such as head trauma, stroke, or severe seizures. This form of epilepsy is often intractable, meaning it is resistant to treatment with antiepileptic drugs. A key area of the brain known as the hippocampus is thought to play a major role in TLE because it is often damaged and surgical removal of this area can improve outcomes. In the present study, our goal is to study a well-defined region of the hippocampus known as the dentate gyrus (DG) since it is considered critical to seizures in TLE. Within the DG there is a special cell type known as mossy cells (MCs) that are thought to normally support DG inhibition. However, MCs also have numerous excitatory connections in the DG that are hypothesized to cause seizures in TLE. Therefore, our goal is to selectively manipulate MCs to determine their effects on DG function and TLE. We will focus on two potentially therapeutic targets expressed by MCs: cannabinoid 1 receptors (CB1Rs) and dopamine D2 receptors (D2Rs). To address antiepileptic effects of CB1R and D2R manipulations, we will genetically overexpress or genetically delete CB1Rs/D2Rs in MCs to determine the effects in a TLE animal model. We will also manipulate MC CB1Rs and D2Rs in vitro to address mechanisms. My long-term career goal is to develop novel treatment options for TLE.
