title: Temperature elevation increases GABA(A) -mediated cortical inhibition in a mouse model of genetic epilepsy.
abstract: A missense mutation (R43Q) in the γ2 subunit of the γ-aminobutyric acid (GABA)(A) receptor is associated with generalized (genetic) epilepsy with febrile seizures plus (GEFS+). Heterozygous GABA(A) γ2(R43Q) mice displayed a lower temperature threshold for thermal seizures as compared to wild-type littermates. Temperature-dependent internalization of GABA(A) γ2(R43Q)-containing receptors has been proposed as a mechanism underlying febrile seizure genesis in patients with this mutation. We tested this idea using the GABA(A) γ2(R43Q) knockin mouse model and analyzed GABAergic miniature postsynaptic inhibitory currents (mIPSCs) in acute brain slices after exposure to varying temperatures. Incubation of slices at an elevated temperature increased mIPSC amplitude in neurons from heterozygous mice, with no change seen in wild-type controls. [³H]Flumazenil binding measured in whole-brain homogenates from mutant and control mice following elevation of body temperature showed no temperature-dependent differences in γ2-containing receptor density. Therefore, in vivo mouse data do not support earlier in vitro observations that proposed temperature-dependent internalization of γ2 R43Q containing GABA(A) receptors as the cellular mechanism underlying febrile seizure genesis in patients with the GABA(A) γ2(R43Q) mutation.
authors.affiliation: Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Elisa L
authors.initials: EL
authors.lastname: Hill
authors.forename: Suzanne
authors.initials: S
authors.lastname: Hosie
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Mulligan
authors.forename: Kay L
authors.initials: KL
authors.lastname: Richards
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Davies
authors.forename: Celine M
authors.initials: CM
authors.lastname: Dubé
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reid
authors.forename: Mathew V
authors.initials: MV
authors.lastname: Jones
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000235:genetics / Q000502:physiology*; D002540:Cerebral Cortex / Q000502:physiology; D004195:Disease Models, Animal; D004829:Epilepsy, Generalized / Q000235:genetics / Q000503:physiopathology*; D055879:Gene Knock-In Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D003294:Seizures, Febrile / Q000235:genetics / Q000503:physiopathology*
chemical_list: D011963:Receptors, GABA-A