Effects of the GABA(A) receptor antagonists bicuculline and gabazine on stimulus-induced sharp wave-ripple complexes in adult rat hippocampus in vitro

Hippocampal sharp wave-ripple-complexes (SPW-Rs) are characterized by slow field potential transients superimposed by ripples with a frequency of ∼200 Hz. In epileptic humans and rats frequencies of such transient network oscillations can reach up to 500 Hz potentially due to loss of functional inhibition. Therefore, we investigated whether GABA_A receptor antagonists increased ripple frequency during SPW-Rs. Within area CA3, SPW-Rs were induced by repeated stimulation of stratum radiatum in area CA1 of adult Wistar rat hippocampal slices. Intracellular recordings showed that in approximately 50% of recorded CA3 pyramidal cells SPW-Rs were accompanied by compound excitory postsynaptic potentials (EPSPs) of ∼10 mV superimposed by up to four action potentials (APs). The remaining cells responded with a compound inhibitory postsynaptic potential (IPSP) during SPW-Rs. The GABA_A receptor antagonists bicuculline (BMI) or gabazine (SR-95531) led to a transition of SPW-Rs into prolonged bursts with a significant increase in amplitude and duration reminiscent of recurrent epileptiform discharges (REDs). Ripple frequencies increased from ∼190 Hz to ∼300 Hz. In naïve slices SR-95531 and BMI also evoked REDs with similar incidence and high frequency ripple frequencies of ∼240 Hz. Elevations in extracellular potassium concentration during REDs were approximately 20-fold higher than those observed during SPW-Rs. Intracellular recordings revealed bursts that were characterized by a large (> 25 mV) prolonged depolarization superimposed by up to 40 APs in close synchrony with extracellularly recorded ripples. Our results suggest that the generation of high frequency ripples, which are also observed in epileptic humans and rats, could indicate a loss of functional inhibition.