In Figure 6, we explored the functional implications of the spatial distribution of SL in PC dendrites receiving four MC axons (48 inhibitory synapses, white dots in Figure 6B; Berger et al., 2010), thus mimicking the MC-to-PC disynaptic “loop” ( Silberberg and Markram, 2007; Berger et al., 2010). The modeled layer 5 PC ( Hay et al., 2011) faithfully replicated the generation of dendritic Ca2+ spikes at a “hot zone” containing a high density of Ca2+ channels (dashed line near the main apical branch). Note that the model includes the increase in the Ih conductance with the distance from soma as was found experimentally ( Kole et al., 2006). Applying synaptic-like

transient excitatory current (Idend in Figure 6C) near the Ca2+ hot zone resulted in the generation of a local Ca2+ spike in the Selleckchem LY2157299 PC model (red trace in Figure 6C), followed by a burst of two somatic Na+ spikes (black traces in Figure 6C; Larkum et al.,

1999). When all 48 inhibitory synapses were activated, both the Ca2+ spike and the resultant Na+ spikes were blocked ( Figure 6D), in agreement with recent experimental results ( Murayama et al., 2009). When the stimulus intensity, Idend, was increased, the local Ca2+ spike check details was recovered but did not generate somatic Na+ spikes ( Figure 6E). Thus, although the inhibitory synapses from MCs did not contact the main apical shaft, MC inhibition effectively electrically decoupled the dendritic Ca2+ spike from the soma as well as decoupled the backpropagation of the Na+ spike from the soma to the dendrites (data not shown).

Therefore, MC inhibition may operate in PC dendrites directly on the Ca2+ spike mechanism and/or on the electrical Oxymatrine interaction between the apical dendrite and the soma ( Figure 6F). The location of MC synapses on the oblique dendrites, as well as on the distal apical branches ( Figure 5D), and the large SL value in these branches suggest that they may serve additional functions, such as dampening local NMDA spikes in these branches. We thus demonstrated that our theoretical predictions for the spread of inhibitory conductance when multiple synapses impinge on the tree hold for the realistic case of the MC-to-PC connection. In particular, SL is elevated in central dendritic regions lacking inhibition, namely the proximal apical trunk, and this elevated inhibition is expected to decouple the two spike initiation zones in L5 pyramidal cells: the soma and/or axon region and the region in the vicinity of the main branch point in the apical tuft. The shunt level, SL, introduced in this study is a simple, intuitive, and analytically tractable measure for assessing the impact of inhibitory conductance change on dendritic cables. Solving the cable equation for SL in arbitrary passive dendritic trees receiving multiple inhibitory contacts has provided several surprising results.