Esser SK, Hill S, Tononi G. Breakdown of effective connectivity during slow wave sleep: investigating the mechanism underlying a cortical gate using large-scale modeling. J Neurophysiol 102: 2096-2111, 2009. First published August 5, 2009; doi: 10.1152/jn.00059.2009. Effective connectivity between cortical areas decreases during slow wave sleep. This decline can be observed in the reduced interareal propagation of activity evoked either directly in cortex by transcranial magnetic stimulation (TMS) or by sensory stimulation. We present here a large-scale model of the thalamocortical system that is capable of reproducing these experimental observations. This model was constructed according to a large number of physiological and anatomical constraints and includes over 30,000 spiking neurons interconnected by more than 5 million synaptic connections and organized into three cortical areas. By simulating the different effects of arousal promoting neuromodulators, the model can produce a waking or a slow wave sleep-like mode. In this work, we also seek to explain why intercortical signal transmission decreases in slow wave sleep. The traditional explanation for reduced brain responses during this state, a thalamic gate, cannot account for the reduced propagation between cortical areas. Therefore we propose that a cortical gate is responsible for this diminished intercortical propagation. We used our model to test three candidate mechanisms that might produce a cortical gate during slow wave sleep: a propensity to enter a local down state following perturbation, which blocks the propagation of activity to other areas, increases in potassium channel conductance that reduce neuronal responsiveness, and a shift in the balance of synaptic excitation and inhibition toward inhibition, which decreases network responses to perturbation. Of these mechanisms, we find that only a shift in the balance of synaptic excitation and inhibition can account for the observed in vivo response to direct cortical perturbation as well as many features of spontaneous sleep.