Excitability and Plasticity of Developing Epileptic Brain

Abstract Our long term goal is to learn how an inherited single gene error produces a specific pattern of epilepsy in the developing brain, to provide an exact description of relevant plasticity within affected neural networks, and to reverse the seizure phenotype at the earliest possible stage. Spike-wave (SW) absence seizures comprise a major category of inherited epilepsy in children, and often herald cognitive deficits and more severe seizures. Over 20 mutant genes for this phenotype are known, and their effects on channel behavior and routes of convergence on excitability within thalamocortical pacemaking circuitry are now more clearly defined. The P/Q calcium channel mouse mutant is a prototype for this analysis, and like other models, shows elevated thalamic T-type calcium currents that are sufficient to generate absence epilepsy, illuminating a shared downstream plasticity pathway triggered by functionally disparate upstream SW genes. The mechanism underlying T-type current remodeling is not understood. In the past project period we narrowed the critical pathogenic microcircuitry and found that selective ablation of P/Q type calcium channels in Layer 6 corticothalamic neurons alone are sufficient to elevate thalamic T currents and cause SW epilepsy, reducing the analysis from the entire brain to a single thalamic afferent synapse, and showed that adult P/Q channel deletion reproduces the childhood syndrome albeit through an alternative pattern of T current circuit remodeling. Using newly created models, we will 1) analyze native and alternative thalamic transcriptome changes to define the molecular basis for T current plasticity in thalamic excitatory and inhibitory neurons and uncover novel epistatic genes participating in this switch, 2) test the thalamic current imbalance in a digenic model to simulate the combinatorial effects of common human CAE variants in T currents, and 3) determine whether we can reverse the T current imbalance and epileptic phenotype in PQ channel mutants by restoring normal PQ function after the onset of seizures. This analysis brings us closer to molecular level treatments of pathogenic gene expression in epilepsy.