Inhibitory nature of tiagabine-augmented GABA(A) receptor-mediated depolarizing responses in hippocampal pyramidal cells

Tiagabine is a potent GABA uptake inhibitor with demonstrated anticonvulsan t activity. GABA uptake inhibitors are believed to produce their anticonvul sant effects by prolonging the postsynaptic actions of GABA, released durin g episodes of neuronal hyperexcitability. However, tiagabine has recently b een reported to facilitate the depolarizing actions of GABA in the CNS of a dult rats following the stimulation of inhibitory pathways at a frequency ( 100 Hz) intended to mimic interneuronal activation during epileptiform acti vity. In the present study, we performed extracellular and whole cell recor dings from CA I pyramidal neurons in rat hippocampal slices to examine the functional consequences of tiagabine-augmented GABA-mediated depolarizing r esponses. Orthodromic population spikes (PSs), elicited from the stratum ra diatum, were inhibited following the activation of recurrent inhibitory pat hways by antidromic conditioning stimulation of the alveus, which consisted of either a single stimulus or a train of stimuli delivered at high-freque ncy (100 Hz, 200 ms). The inhibition of orthodromic PSs produced by high-fr equency conditioning stimulation (T-IFS), which was always of much greater strength and duration than that produced by a single conditioning stimulus, was greatly enhanced following the bath application of tiagabine (2-100 mu M). Thus, in the presence of tiagabine (20 mu M), orthodromic PSs, evoked 100 and 800 ms following HFS, were inhibited to 7.8 +/-: 2.6% (mean +/- SE) and 33.4 +/- 18.59 of their unconditioned amplitudes compared with only 35 .4 +/- 12.7% and 98.8 +/- 12.4% in control. Whole cell recordings revealed that the hath application of tiagabine (20 mu M) either caused the appearan ce or greatly enhanced the amplitude of GABA-mediated depolarizing response s (DR). Excitatory postsynaptic potentials (EPSPs) evoked from stratum radi atum at time points that coincided with the DR were inhibited to below the threshold for action-potential firing. Independently of the stimulus intens ity with which they were evoked, the charge transferred to the soma by exci tatory postsynaptic currents (EPSCs), elicited in the presence of tiagabine (20 mu M) during the large (1,428 +/- 331 pA) inward currents that underli e the DRs, was decreased on the average by 90.8 +/- 1.7%. Such inhibition o ccurred despite the presence of the GABA(B) receptor antagonist, CGP 52 432 (10 mu M), indicating that GABA(B) heteroreceptors, located on glutamaterg ic terminals, do not mediate the observed reduction in the amplitude of exc itatory postsynaptic responses. The present results suggest that despite fa cilitating the induction of GABA-mediated depolarizations, tiagabine applic ation may nevertheless increase the effectiveness of synaptic inhibition du ring the synchronous high-frequency activation of inhibitory interneurons b y enhanced shunting.