1. Dual intracellular recordings of granule cells, hilar interneurons and CA3 pyramidal cells were performed in transverse slices of guinea-pig hippocampus. At resting membrane potential, in the presence of 4-aminopyridine, ionotropic glutamate receptor antagonists and the GABAA receptor antagonist bicuculline, granule cells showed spontaneous, large amplitude depolarizations correlated with synchronous bursting activity of interneurons. 2. Under these conditions, pyramidal cells exhibited large amplitude monophasic GABAB inhibitory postsynaptic potentials (IPSPs) synchronous with the GABAergic interneuron burst discharges. The granule cells also received a GABAB input, which was evident only when the neurons were depolarized by DC injection. The GABAB receptor antagonist CGP 55,845A (CGP) blocked the GABAB IPSPs in both pyramidal cells and granule cells; however, the depolarizing potential in granule cells was unaffected by the drug. 3. The granule cells depolarization in the presence of CGP was monophasic and exhibited linear voltage dependence with a reversal potential around -40 mV, suggesting that it was generated by a synaptic input activating a mixed cationic current. 4. The granule cell depolarization was abolished following the addition of tetrodotoxin to the bath. In addition, perfusing the slice with a low Ca(2+)-containing solution (0.5 mM Ca(2+)-10 mM Mg2+) also abolished the granule cell depolarization, confirming the synaptic origin of the event. 5. (S)-Methyl-4-carboxyphenylglycine, L-(+)-2-amino-3-phosphonopropionic acid, propranolol and atropine did not affect the granule cell depolarization, indicating that metabotropic glutamate receptors, beta-adrenergic receptors and muscarinic cholinergic receptors were not involved in generating the granule cell depolarizing synaptic response. 6. These findings indicate that, in the absence of both glutamatergic and GABAergic inputs, synchronous interneuronal activity can produce a depolarizing synaptic response in granule cells. The neurochemical responsible for the depolarization is currently under investigation.