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 SW genes. The mechanism underlying T-type current remodeling is not understood. In the past project period we have narrowed the critical pathogenic microcircuitry and found that selective ablation of P/Q type calcium channels in Layer 6 corticothalamic neurons only is sufficient to elevate thalamic T currents and cause SW epilepsy, reducing the analysis from the entire brain to a single synapse. Using this streamlined model, we now seek to define the developmental onset of postsynaptic thalamic ion channel remodeling to pinpoint a postnatal window of therapeutic opportunity.
In Aim 1 we will examine the role of corticothalamic presynaptic release defects versus postsynaptic excitability on intrinsic channel modulation, and the timing of this event relative to a programmed developmental N/PQ channel switch for neurotransmitter release.
In Aim 2 we explore structural implications in thalamic cells.
In Aim 3 we analyze thalamic transcriptome changes linked to T current modulation.
In aim 4 we test druggable targets that may prevent or reverse T channel remodeling. This analysis brings us closer to molecular control of disease gene expression in epilepsy.
This project will determine more precisely how mutation of a single ion channel gene causes a specific inherited seizure pattern, which neuronal circuits may be critically involved, and when it appears during brain development. A downstream plasticity mechanism underlying the pathological transformation of thalamocortical network firing from normal rhythms to abnormal burst firing patterns has been isolated that can explain how different genes lead to the same phenotype. The critical timing and pharmacological reversibility of this mechanism will be analyzed. These findings may lead to novel and even preventative treatments for the most common form of childhood epilepsy.
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