If tuft excitatory synaptic input is isolated from the axon, and only weakly directly drives apical dendritic trunk spike initiation, how can it influence neuronal output? We demonstrate that the apical dendritic tuft can interact in

a nonlinear manner with more proximal integration zones (i.e., the axon and nexus), and that KV channels control this process. Previous findings have revealed that axosomatic and dendritic trunk integration compartments can synergistically interact in L5B pyramidal neurons (Larkum et al., 1999, Larkum et al., 2004 and Williams, 2005). Here, we show that apical dendritic KV channels tightly control this selleck inhibitor interaction. Indeed, KV channels also governed the interaction between subthreshold tuft excitatory input and trunk spike generation, with the pharmacological blockade of KV channels leading to the generation

of large amplitude long-duration plateau potentials in the apical dendritic arbor. As apical dendritic KV channels exhibit highly sensitive voltage- and time-dependent inactivation properties, widespread depolarization of the apical dendritic MAPK inhibitor tuft, as may occur during behavior (Xu et al., 2012), will lead to voltage-dependent KV channel inactivation, that is augmented by the local recruitment of NMDA-receptor- and Na+-channel-mediated supralinearities. These effects will powerfully influence the interaction between axosomatic and apical dendritic of trunk integration compartments. Consistent with this, we find that tuft Ca2+ signals during behavior are enhanced by pharmacological blockade of KV channels. These observations support a multilayer integration scheme for L5B pyramidal neurons, which we tested experimentally using triple recordings. Top-down, apical tuft excitatory input was found to decisively

influence the rate and pattern of AP firing evoked via coincident activation of axosomatic and apical dendritic trunk integration compartments by controlling the duration of apical dendritic plateau potentials. Therefore, trunk spikes are not a binary output mode of apical dendritic integration, but rather are analog signals, the duration of which is tuned by apical dendritic tuft excitatory input. Our direct demonstration that apical dendritic tuft input drives high-frequency AP burst firing suggests that top-down influences such as attention, expectation, and action command (Gilbert and Sigman, 2007, Gregoriou et al., 2009, Hupe et al., 1998 and Xu et al.