Due to the asymmetry in the boundary conditions, the distal synapse induces a larger hyperpolarization at the hotspot compared to the proximal synapse. Both the larger hyperpolarization and the larger SL at the hotspot generated by the distal synapse are combined to enhance its inhibitory impact on the hotspot (and thus on the soma firing) as compared to the proximal synapse ( Figure 2C and see more detailed analysis in Figures S5–S7). These results are also valid for different

loci with respect to the hotspot of the inhibitory synapses along the dendritic cable model ( Figure S5). Note that the results in Figures 1 and 2 hold for any dendritic region producing High Content Screening inward current (e.g., via an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA]

synapse). But the advantage of distal versus proximal inhibition at that region is amplified in the voltage-dependent (nonlinear) case (e.g., NMDA currents as in Figures 1B and 2B or active Ca+2 or Na+ inward currents) because inhibition at the hotspot this website increases the threshold for the activation of regenerative inward currents (Jadi et al., 2012). We also note that the advantage of the “off-path” inhibition over the corresponding “on-path” inhibition in dampening a local dendritic hotspot is augmented in distal thin dendrites because, in such branches, the asymmetry in (distal versus proximal) boundary conditions is even larger than the cylindrical case modeled in Figures 1 and 2 (Rall

and Rinzel, 1973). Figure 3 depicts SL in the case of an idealized branched dendritic tree ( Rall and Rinzel, 1973) receiving Histone demethylase a single conductance perturbation in a distal dendritic terminal. For comparison, the steady voltage (V, dotted line) attenuation is also shown. V attenuation is steep from the distal (input) branch toward the branch point (P) but is shallow in the direction of the sibling branch S ( Figure 3, black arrow) because of the sealed-end boundary condition in this branch ( Rall and Rinzel, 1973; Golding et al., 2005). Similarly to V, SL attenuates steeply toward the soma; however, in contrast to V, SL attenuates steeply toward terminal S (blue line). This follows directly from Equation 3, as SL attenuation from P to S depends on the (steep) voltage attenuation from S to P (AS,P). Consequently, the impact of conductance perturbation diminishes rapidly with distance in such thin dendritic branches. Hence, excitatory currents in distal dendrites are electrically “protected” from the inhibitory shunt, unless the inhibitory synapses directly target these branches. In the realistic case, the dendritic tree receives multiple inhibitory synapses; even a single inhibitory axon typically contacts the postsynaptic dendritic tree at multiple loci, often making more than ten synapses in the postsynaptic dendritic tree (Markram et al., 2004).