Fast oscillations at *200 Hz, termed ripples, occur in the hippocampus and cortex of several species, including humans, and are thought to play a role in physiological (e.g., sensory information processing or memory consolidation) and pathological (e.g., seizures) processes. Blocking g-aminobutyric acid type A (GABA A ) receptor-mediated inhibition represents one of the most often used models of epileptiform discharge. Here we found that bath application of the GABA A receptor antagonist picrotoxin (50 mM) to mouse hippocampusentorhinal cortex slices induced spontaneous epileptiform activity (duration 536.6 6 146.1 msec, mean 6 SD; interval of occurrence 14.8 6 3.3 sec, n ¼ 12) with two distinct phases of discharge; the first was characterized, in the dentate gyrus only, by high-frequency, field oscillations (ripples) at 206.3 6 23.4 Hz (n ¼ 12), whereas the second component corresponded to afterdischarges in the theta range frequency. Ripples, which were also recorded in ''minislices'' only of the dentate gyrus, were unaffected by application of the m-opioid receptor agonist (D-Ala2-N-Me-Phe,Gly-ol)enkephalin (10 mM; n ¼ 6) or the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxy-piperazine-4-yl)-propyl-l-phosphonate (10 mM; n ¼ 5). In contrast, the non-NMDA glutamatergic receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (10 mM; n ¼ 5) completely blocked all picrotoxin-induced activities. In addition, application of the GABA B receptor agonist baclofen (0.01-0.5 mM; n ¼ 6) dose dependently and reversibly abolished all picrotoxin-induced activities. We also found that application of the gap-junction decouplers carbenoxolone (0.2-0.5 mM; n ¼ 6) or octanol (0.2-0.5 mM; n ¼ 3) blocked the second phase while leaving ripples unchanged. These findings demonstrate that the disinhibited dentate gyrus can generate ripple activity at *200 Hz that is contributed by ionotropic glutamatergic mechanisms and is not dependent on either GABA A receptor-mediated or gap-junction mechanisms.