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Synaptic Depolarizing GABA Response in Adults Is Excitatory and Proconvulsive When GABA_B Receptors Are Blocked

¹Department of Physiology and Pharmacology and ²Program in Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, New York

Submitted 29 September 2004; accepted in final form 2 December 2004

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.

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