Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices expressing a C-terminal truncated GABA(B2) receptor subunit.
GABAergic synaptic transmission plays an important role in the patterning of epileptiform activity. We have previously shown that global loss of GABA(B) receptor function due to transgenic deletion of the GABA(B1) receptor subunit exacerbates epileptiform activity induced by pharmacological manipulations in hippocampal slices. Here we show that a similar hyperexcitable phenotype is observed in hippocampal slices prepared from a transgenic mouse expressing a GABA(B2) receptor subunit lacking its C terminal tail (the DeltaGB2-Ct mouse); a molecular manipulation that also produces complete loss of GABA(B) receptor function. Thus, epileptiform bursts that are sensitive to NMDA receptor antagonists (induced by either the GABA(A) receptor antagonist bicuculline (10muM) or removal of extracellular Mg(2+)) were significantly longer in duration in DeltaGB2-Ct slices relative to WT slices. We now extend these observations to demonstrate that a stimulus train induced bursting (STIB) protocol also evokes significantly longer bicuculline sensitive bursts of activity in DeltaGB2-Ct slices compared to WT. Furthermore, synchronous GABA(A) receptor-mediated potentials recorded in the presence of the potassium channel blocker 4-aminopyridine (4-AP, 100muM) and the ionotropic glutamate receptor antagonists NBQX (20muM) and D-AP5 (50muM) were significantly prolonged in duration in DeltaGB2-Ct versus WT slices. These data suggest that the loss of GABA(B) receptor function in DeltaGB2-Ct hippocampal slices promotes depolarising GABA(A) receptor-mediated events, which in turn, leads to the generation of ictal-like events, which may contribute to the epilepsy phenotype observed in vivo.
Neurology and GI CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. sjt2104@columbia.edu
Sébastien J
SJ
Thuault
Jon T
JT
Brown
Andrew R
AR
Calver
Graham L
GL
Collingridge
Andrew
A
Randall
Ceri H
CH
Davies
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D008274:Magnesium / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010721:Phosphinic Acids / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D017966:Pyramidal Cells; D011806:Quinolinium Compounds / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D010721:Phosphinic Acids; D026902:Potassium Channel Blockers; D011412:Propanolamines; D011806:Quinolinium Compounds; D018080:Receptors, GABA-B; C085075:CGP 55845A; C056639:2-amino-5-phosphopentanoic acid; C038668:3-nitrobenzothiazolo(3,2-a)quinolinium; D015761:4-Aminopyridine; D014633:Valine; D008274:Magnesium; D001640:Bicuculline