Our long term goal is to learn how an inherited gene error produces a specific pattern of epilepsy in the developing brain, to provide an exact description of seizure-induced plasticity within affected neural networks, and in this project period, to isolate intervening candidate network mechanisms by selective genetic rescue. Generalized spike-wave absence seizures comprise a major category of inherited epilepsy in children. Although mutant genes for this phenotype and their effects on ion channel behavior are known, their routes of convergence on downstream neuronal excitability mechanisms in pacemaking circuitry are only beginning to be clearly defined. The goal of this project is to examine specific network abnormalities identified in stargazer (y2) mutant mice and other voltage-gated calcium channel and transmitter release- defective mutants with spike-wave seizures. The stargazer gene product y2 (stargazin) interacts with calcium channels and AMPA type glutamate receptors. Previously we identified membrane excitability, release defects, and other plasticity in thalamic neurons in vivo and in vitro that precede the developmental onset of epilepsy. We now hypothesize that: (1) that epileptic hypersynchrony in these mice arises from distinct thalamocortical excitability defects that alter pacemaking membrane currents and impair synaptic transmission, and (2) that inhibitory and excitatory synapses are differentially affected by these channelopathies. Using patch clamp, optical recordings, molecular anatomy, and transgenic methods, we will test specific hypotheses regarding the cellular mechanisms underlying the network defect. We will explore the functional role of the gene-linked defects in epileptogenesis by determining which components of the phenotype arise as a primary cellular expression of the channelopathy and which are a product of neuroplasticity.
In aims 1 and 2 we will continue to use cell type-specific transgenic rescue strategies to dissect the role of interneurons and transmitter release, and explore how co-existing monogenic channelopathies may interact.
In aims 3 and 4, we further explore the role of enhanced T-type currents using bac-transgenes. These studies directly test key hypotheses concerning basic mechanisms of aberrant thalamocortical oscillations produced by inherited gene mutations, and the degree of long-term cellular and molecular neuroplasticity that may accompany early seizures of the spike-wave pattern. This project will determine how a mutation of a single gene causes a specific pattern of epilepsy in the brain, which brain circuits are involved, and when it appears during development. Gene interactions that may prevent seizures from appearing are also explored, and may help predict the risk of childhood epilepsy.
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