title: Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy.
abstract: Mutations in the GABA(A) receptor gamma2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a gamma2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of gamma2(R43Q) was seen in heterozygous mice in the absence of any change in alpha1 subunit surface expression, ruling out a dominant-negative effect. GABA(A)-mediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.
authors.affiliation: Howard Florey Institute, University of Melbourne, Parkville 3010, Australia.
authors.forename: Heneu O
authors.initials: HO
authors.lastname: Tan
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reid
authors.forename: Frank N
authors.initials: FN
authors.lastname: Single
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Davies
authors.forename: Cindy
authors.initials: C
authors.lastname: Chiu
authors.forename: Susan
authors.initials: S
authors.lastname: Murphy
authors.forename: Alison L
authors.initials: AL
authors.lastname: Clarke
authors.forename: Leanne
authors.initials: L
authors.lastname: Dibbens
authors.forename: Heinz
authors.initials: H
authors.lastname: Krestel
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.forename: Mathew V
authors.initials: MV
authors.lastname: Jones
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeburg
authors.forename: Bert
authors.initials: B
authors.lastname: Sakmann
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005013:Ethosuximide / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D051379:Mice; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D011963:Receptors, GABA-A; D005013:Ethosuximide