title: Synaptic depolarizing GABA Response in adults is excitatory and proconvulsive when GABAB receptors are blocked.
abstract: In the presence of 4-aminopyridine, interneurons fire synchronously, causing giant GABA-mediated postsynaptic potentials (GPSPs; GPSCs in voltage clamp) in CA3 pyramidal cells in hippocampal slices from adult guinea pigs. These triphasic GPSPs are composed of a GABA(A)-mediated hyperpolarizing component, a depolarizing component, and a GABA(B)-mediated hyperpolarizing component. We propose that GABA(B) receptors exert control over the postsynaptic depolarizing GABA response. Microelectrode and cell-attached recordings demonstrated that the mean number of action potentials during the depolarizing component of the GPSP increased dramatically in the presence of the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2- hydroxypropyl](phenylmethyl) phosphinic acid (CGP 55845A; P = 0.003 and 0.0005, respectively). Whole cell voltage-clamp recordings showed that the postsynaptic GABA(B) and depolarizing GABA components of the GPSC overlap substantially, allowing the GABA(B)-mediated hyperpolarization to suppress the excitation mediated by the depolarizing GABA component. Further voltage-clamp recordings showed that CGP 55845A increased the duration of the depolarizing GABA component of the GPSC even when the GABA(B) component had already been blocked by internal QX-314, suggesting that CGP 55845A also increased the duration of GABA release. When glutamatergic transmission is intact, GPSPs directly precede epileptiform afterdischarges. We hypothesize that the depolarizing component of the GPSP triggers the epileptiform events and show here that enhancement of the depolarizing component with CGP 55845A increased epileptiform activity. CGP 55845A increased the likelihood of a GPSP triggering an epileptiform event from 32 to 99% (P = 0.0000001), and significantly increased the number of afterdischarges per epileptiform event (P = 0.001). Loss of GABA(B) receptor function is associated with temporal lobe epilepsy in rodents and humans. We show here that GABA(B) receptors exert control over the synaptic depolarizing GABA response and that block of GABA(B) receptors makes the depolarizing GABA response excitatory and proconvulsive.
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Kantrowitz
authors.forename: N Noelle
authors.initials: NN
authors.lastname: Francis
authors.forename: Alejandro
authors.initials: A
authors.lastname: Salah
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Perkins
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010721:Phosphinic Acids / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000779:Anesthetics, Local; D018756:GABA Antagonists; D010721:Phosphinic Acids; D026902:Potassium Channel Blockers; D011412:Propanolamines; D011724:Pyridazines; D011963:Receptors, GABA-A; C085075:CGP 55845A; C012647:QX-314; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D008012:Lidocaine; C049853:gabazine; D015761:4-Aminopyridine