Mechanisms of Epileptogenesis and Circuit Dysfunction in a Mouse Model of TSC
Abstract
Epilepsy in tuberous sclerosis complex (TSC) is often resistant to traditional anti-epileptic drugs and to mTOR inhibitors. We understand very little about how brain circuits in TSC become epileptic or drug-resistant in part because fluctuations in gene expression during the development of epilepsy present a moving target. It is not known if the gene expression status of epileptic brain circuits after epilepsy onset is involved in generating seizures or if it is a secondary consequence of seizure activity. Surgically removed brain tissue from TSC patients with drug-resistant epilepsy has provided valuable information about alterations in gene expression and the electrical properties of neurons. However, these changes only offer a snapshot of gene expression during a late phase of epilepsy, which may be a secondary consequence of seizure activity. These changes also cannot be compared reliably against “normal tissue” because it is often taken from the same TSC patient. It is therefore difficult to tease apart the various components of a neuron’s function and structure responsible for epilepsy or drug resistance. The structure and function of a brain circuit early after the onset of epilepsy may be different from that late in the course of epilepsy when seizures are drug-resistant. Structure and function rely on gene expression. If we can compare gene expression of neurons at these early and late time points after the development of epilepsy, including when seizures are drug-resistant, we may be able to identify important genes and proteins involved in drug-resistant seizures. The TSC mouse model we are using in the proposed studies exhibits severe epilepsy and responds to mTOR inhibitor, a common treatment for TSC patients. However, just like in TSC patients, mTOR inhibitors in this mouse are transiently effective but seizures re-emerge even when starting treatment very early in the life and after re-emergence are drug-resistant. The seizure suppression and its subsequent resurgence in this mouse model provide an excellent opportunity to explore neuronal circuit deficits and gene expression alterations associated with drug resistance. Our goal is to understand the mechanisms underlying drug-resistant seizures in TSC and thereby gain insights into novel therapeutic targets that would potentially be disease modifying for this aspect of the TSC phenotype. Seizures result from an imbalance in excitatory and inhibitory neurotransmission. Restoring the excitatory/inhibitory balance is critical for decreases excitability of the epileptic neuronal circuits. Different types of brain cells contribute to this balance, with each having a unique gene expression profile. Therefore, it is important to carefully examine the gene expression status at the level of cell type in an epileptic circuit. The technique we are using, which has not been applied in the field of TSC except in our recent studies in human TSC brain tissue resected in epilepsy surgery, examines the electrical properties of multiple neurons at the same time and then plucks out all gene products from each neuron. The comprehensive gene expression profile of each neuron can then be correlated with its structure and function. We will look at these neurons early and late after the onset of epilepsy, with the late time points including after the development of drug-resistant seizures. This approach will allow us to see what gene products were active when there were few seizures and what gene products were active after the onset of seizures that were drug-resistant at the level of cell type. We will also see what gene products remain or become active during drug resistance. The field of TSC currently only has a short list of genes with presumed roles in epilepsy and an even shorter list of medications against drug-resistant epilepsy. We hope that our studies will generate a resource of gene expression profiles at the level of cell type early and late in the course of epilep
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110366
Entities
People
- Anne Anderson
Organizations
- Baylor College of Medicine
- United States Army