Recordings were obtained from neurons in layer II/III of slices of rat frontal cortex maintained in vitro. We investigated whether brief application of the potassium channel blocker tetraethylammonium (TEA), which induces a novel form of synaptic plasticity in the CA1 region of the hippocampus referred to as LTPk evokes similar responses in neocortex. Consistent with previous findings, TEA produced a persistent enhancement of excitatory transmission, which was independent of NMDA receptor activation but required the activation of nifedipine-sensitive voltage-dependent Ca2+ channels (VDCC), presumably the L-type. We also observed a persistent enhancement of presumptive Cl-dependent GABAA receptor-mediated transmission. Enhancement of excitatory and inhibitory synaptic transmission did not require activation of synapses with electrical stimulation during TEA application. The enhancement of excitatory, but not inhibitory synaptic transmission, was blocked when the Ca2+ chelator 1,2-bis(2-aminophenoxy)-ethane N,N,N′,N′-tetraacetic acid (BAPTA) was included in the recording electrode. Under voltage clamp conditions that minimized the activation of L-type channels robust enhancement of both excitatory and inhibitory transmission was still observed. No enhancement of excitatory synaptic transmission was observed in the presence of NiCl2, a putative T-type channel blocker. The possible involvement of kinase activation was studied by including the non-specific and competitive kinase inhibitor (±)-1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) in the patch pipette. H-7 retarded the time course and reduced the magnitude of the enhancement of excitatory transmission. These results suggest that TEA-induced enhancement of excitatory transmission in the neocortex requires entry of Ca2+ into the postsynaptic neuron via VDCCs and possibly the activation of a kinase.