title: Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices of GABAB1 receptor subunit knockout mice.
abstract: The recently developed GABAB1 receptor subunit knockout (GABAB1 -/-) mouse displays complete loss of GABAB receptor function and develops complex generalized epilepsies including absence type, audiogenic as well as spontaneous generalized seizures with electrographic spike-wave discharge signatures. To gain insight into the cellular mechanisms contributing to the generation and maintenance of this epileptic phenotype we have compared epileptiform activity induced in hippocampal slices obtained from GABAB1 -/- and wild type (GABAB1 +/+) littermates. Deletion of the GABAB1 receptor subunit had no effect on a range of passive membrane properties of CA3 pyramidale neurones, non-synaptic epileptiform field bursting and spreading depression recorded in 6mM K+/Ca2+-free medium, and inter-ictal synaptically-induced epileptiform activity induced by 100 microM 4-aminopyridine (4-AP). In contrast, synaptic epileptiform activity induced by 10 microM bicuculline, removal of extracellular Mg2+ or addition of 10 microM oxotremorine was enhanced in GABAB1 -/- slices. Acute blockade of GABAB receptors using a selective antagonist only partly mimicked these effects. It is suggested that the exaggerated in vitro epileptiform activity is caused by both acute and chronic consequences of the loss of GABAB receptor function in vivo. Specifically, enhancement of N-methyl-d-aspartate (NMDA) receptor triggered synaptic processes, arising from the loss of the GABAB receptor-mediated inhibitory postsynaptic potential (IPSP, together with a possible promotion of depolarising IPSPs due to the removal of GABAB autoreceptor function) is likely to underlie these effects.
authors.affiliation: Neurology CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Jon_2_Brown@gsk.com
authors.forename: Jon T
authors.initials: JT
authors.lastname: Brown
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Gill
authors.forename: Clare E
authors.initials: CE
authors.lastname: Farmer
authors.forename: Christophe
authors.initials: C
authors.lastname: Lanneau
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Randall
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
mesh_terms: D000818:Animals; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000172:deficiency* / Q000235:genetics
chemical_list: D058788:GABA-B Receptor Antagonists; D010721:Phosphinic Acids; D011412:Propanolamines; D018080:Receptors, GABA-B; C085075:CGP 55845A