Rasmussen's syndrome (RS) is a rare disease of unknown cause characterized by progressive destruction of a single cerebral hemisphere. The disease typically begins in the first decade of life and is manifested by severe seizures and progressive loss of functions subserved by the involved hemisphere. Recent evidence suggests that an immune response targeting a glutamate receptor of the AMPA subtype, GR3, contributes to RS. The occurrence of epileptic seizures and inflammatory histopathology in two rabbits immunized with a GR3 fusion protein led to the discovery of anti-GR3 in patients with active RS. The investigators have confirmed and extended their original findings by demonstrating that a subset of rabbits immunized with a GR3 fusion protein develop a neurologic disorder that includes epileptic seizures and inflammatory histopathology. Anti-GR3 isolated from GR3 immunized rabbits promote destruction of rat cortical cells in vitro. The objective of this proposal is to test one aspect of the unifying hypothesis of the etiology and pathogenesis of RS, namely that access of anti-GR3 to antigen in the central nervous system produces seizures and cell death. A diversity of electrophysiologic, anatomic and molecular neurobiologic techniques will be employed in both in vivo and in vitro studies.
Specific aim 1 To characterize the animal model of RS observed in our preliminary studies.
Specific aim 2 To determine whether GR3 immunization-induced circulating antidestruction of a single cerebral hemisphere.
Specific aim 3 To determine whether passive transfer of anti-GR3 in vivo can induce epileptic seizures and cell death.
Specific aim 4 To characterize the anti-GR3 raised in specific aims 1 and 2 with respect to titer, subunit specificity, and both agonist and cytotoxic properties. These experiments will facilitate study of mechanisms operative in RS in humans and may lead to novel therapies for the disorder.
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