Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca²⁺-activated K⁺-mediated after hyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg²⁺-free ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A down-regulation of the medium after hyperpolarization (mAHP) paralleled the emergence of the interictal-like activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow after hyperpolarization (sAHP) with carbachol, t-ACPD or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with a KMeSO₄ reduced burst frequency. Block of GABA_AB inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where (i) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, (ii) the sAHP sets the interburst interval by decreasing excitability and (iii) bursting was synchronized via excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity.