These findings yielded several new insights regarding the functional implications of the unique connectivity pattern of dendritic inhibition. Importantly, although these insights are based on the analytical

solution for the steady-state case and for passive dendrites ( Figures 1, 2, and S1–S3), they nevertheless explain simulated results ABT-888 chemical structure obtained for corresponding nonlinear and transient cases. In particular, we analyzed in detail the case of an MC-to-PC inhibitory connection in layer 5 of the neocortex ( Figures 5 and 6), whereby the MC’s inhibitory synapses contact the distal apical dendrites of the PC. Near the main apical branch of the PC, a powerful Ca2+ spike could be evoked; this spike interacts reciprocally with the soma to generate a burst of Na+ spikes Dabrafenib manufacturer at the soma (BAC firing; Larkum et al., 1999). Although the MC’s synapses are more distal than the Ca2+ spike initiation region, we showed that they do effectively dampen the Ca2+ spike (see Figure S12) and also electrically decouple the apical dendrite from the soma, as expected from our analysis of the corresponding passive

case. The effective spread of SL into the dendritic region surrounded by multiple inhibitory synapses ( Figures 4 and 5) leads to a spatially extended shunted dendritic domain beyond the anatomical domain demarcated by these synapses. This spatial spread of inhibitory shunt implies that in order to dampen excitatory and/or excitable dendritic currents, it is not necessary to match each excitatory synapse with a corresponding adjacent inhibitory synapse. Rather, by surrounding a dendritic region with a few inhibitory contacts,

it is possible to effectively dampen the excitatory and/or excitable current that would be generated in this region ( Figures 5 and 6) and thereby effectively control the neuron’s output. This may explain why in the neocortex and the hippocampus, only ∼20% of the synapses are inhibitory ( DeFelipe Adenosine and Fariñas, 1992; Megías et al., 2001; Merchán-Pérez et al., 2009). Due to the extended centripetal spread of the inhibitory shunt, different functional dendritic domains may interact with each other and be formed dynamically by recruiting and/or omitting various combinations of inhibitory synapses at strategic loci. For example, when each of the group of five inhibitory synapses in Figure 4A is individually active, then the functional dendritic subdomain corresponding to each inhibitory subgroup is spatially restricted. However, when all three inhibitory groups of synapses are active together, as in Figure 4A, then the functional dendritic domain that is shunted by the 15 inhibitory synapses expands dramatically, effectively controlling the excitatory and/or excitable charge (output) from a large portion of the postsynaptic dendritic tree.