Gamma-vinyl GABA reduces paired pulse inhibition in the rat dentate gyrus in vivo and in vitro.

Gamma vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, has anticonvulsant effects. GVG increases GABA levels in the brain by blocking its degradation, and is presumed to enhance GABAergic inhibition, however, in some cases it exacerbates seizures. We investigated the effects of GVG in vivo and in vitro on paired pulse inhibition (PPI) recorded in the rat dentate gyrus (DG) evoked by perforant path stimulation. At 2.5 h and 24 h after administration of GVG (1 g/kg, i.p.), there was a loss of PPI at both 15- and 25-ms interpulse intervals (IPI). Activation of presynaptic GABA(B) autoreceptors could explain this in vivo effect. We therefore further investigated the effects of co-application of GVG with the GABA(B) antagonists 2-OH saclofen (saclofen) or CGP 35348 (CGP) on PPI in hippocampal slices by in vitro study. Bath application of GVG (400 and 500 microM) not only resulted in a loss of perforant path evoked PPI at a 15-ms IPI, but produced facilitation of the second population spike relative to the first. Co-application of saclofen (250 microM) with GVG (500 microM) prevented facilitation of the second response of a paired-pulse. The facilitation of the second stimulation response produced by GVG (400 microM) was converted to inhibition by bath application of CGP 35348 (400 microM). These results suggest that activation of presynaptic GABA(B) receptors by increased extracellular GABA may be one of the contributing factors to the apparent paradoxical effect of GVG on PPI in the DG

Masking Synchronous GABA‐mediated Potentials Controls Limbic Seizures

Summary:  Purpose: We determined how CA3‐driven interictal discharges block ictal activity generated in the entorhinal cortex during bath application of 4‐aminopyridine (4AP, 50 μM).Methods: Field potential and [K+]o recordings were obtained from mouse combined hippocampus–entorhinal cortex slices maintained in vitro.Results: 4AP induced N‐methyl‐d‐aspartate (NMDA) receptor–dependent ictal discharges that originated in the entorhinal cortex, disappeared over time, but were reestablished by cutting the Schaffer collateral (n = 20) or by depressing CA3 network excitability with local application of glutamatergic receptor antagonists (n = 5). In addition, two types of interictal activity occurred throughout the experiment. The first type was CA3 driven and was abolished by a non‐NMDA glutamatergic receptor antagonist. The second type was largely contributed by γ‐aminobutyric acid type A (GABAA) receptor–mediated conductances and persisted during blockade of glutamatergic transmission. The absence of CA3‐driven interictal discharges in the entorhinal cortex after Schaffer collateral cut facilitated the GABA‐mediated interictal potentials that corresponded to large [K+]o elevations and played a role in ictal discharge initiation. Accordingly, ictal discharges along with GABA‐mediated interictal potentials disappeared during GABAA‐receptor blockade (n = 7) or activation of μ‐opioid receptors that inhibit GABA release (n = 4).Conclusions: Our findings suggest that CA3‐driven interictal events restrain ictal discharge generation in the entorhinal cortex by modulating the size of interictal GABA‐mediated potentials that lead to large [K+]o elevations capable of initiating ictal discharges in this structure