Modular propagation of epileptiform activity: evidence for an inhibitory veto in neocortex.

What regulates the spread of activity through cortical circuits? We present here data indicating a pivotal role for a vetoing inhibition restraining modules of pyramidal neurons. We combined fast calcium imaging of network activity with whole-cell recordings to examine epileptiform propagation in mouse neocortical slices. Epileptiform activity was induced by washing Mg2+ ions out of the slice. Pyramidal cells receive barrages of inhibitory inputs in advance of the epileptiform wave. The inhibitory barrages are effectively nullified at low doses of picrotoxin (2.5-5 microM). When present, however, these inhibitory barrages occlude an intense excitatory synaptic drive that would normally exceed action potential threshold by approximately a factor of 10. Despite this level of excitation, the inhibitory barrages suppress firing, thereby limiting further neuronal recruitment to the ictal event. Pyramidal neurons are recruited to the epileptiform event once the inhibitory restraint fails and are recruited in spatially clustered populations (150-250 microm diameter). The recruitment of the cells within a given module is virtually simultaneous, and thus epileptiform events progress in intermittent (0.5-1 Hz) steps across the cortical network. We propose that the interneurons that supply the vetoing inhibition define these modular circuit territories.