, 2001 and Stuart and Spruston, 1998). We found that the dendritic input-output function in L5 pyramidal cells was supralinear and sigmoidal with a similar increase in steepness from proximal to distal locations compared with layer 2/3 pyramidal cells (Figures 4A and 4B). As in layer 2/3 pyramidal cells, temporal summation in layer 5 pyramidal cells was much more effective

at distal locations (peak EPSP at 8 ms intervals was 97% ± 2% of the peak at 1 ms intervals for distal synapses, while for proximal locations the peak decreased to 73% ± 8%; p = 0.019, ANOVA; n = 6; Figures 4C and 4D). Blocking Ih channels caused a hyperpolarization of the somatic membrane potential by 9.1 ± 0.2 mV (cf. Berger et al., 2001 and Stuart and Spruston, 1998), accompanied by a dramatic reduction in the degree of supralinearity (35% ± 3% of control; p < 0.0001; n = 5; Figures 4E and 4G) and efficacy of temporal summation (59% ± 13% of control for distal dendrites; this website p = 0.036; n = 5; Figures 4F and 4G). However, somatic depolarization via current injection restored the supralinearity (104% ± 19% of control; p = 0.85) as well as temporal summation (100% ± 6% of control; p = JQ1 research buy 0.95). This suggests

that in layer 5 pyramidal cells, the interaction between dendritic nonlinearities and the depolarizing effect of Ih can overcome the Ih-dependent speeding of the EPSP decay. Thus, as in layer 2/3 pyramidal cells, layer 5 pyramidal cell dendrites exhibit increased gain and temporal summation

at distal sites. To further explore the biophysical basis of integration gradients in cortical pyramidal cell dendrites, we constructed a compartmental model of a layer 2/3 pyramidal cell (Figure 5A). Passive properties were adjusted to match our recordings, and active conductances were distributed in all compartments according to previous studies (Major et al., 2008 and Nevian Endonuclease et al., 2007; see Experimental Procedures). Synapses containing both AMPARs and NMDARs were placed at different locations along an individual dendrite. As in our experiments, we increased the number of activated synapses or the intersynapse stimulation interval while recording the somatic EPSP (Figures 5B and 5C). The simulation results closely matched the experimental data, showing sigmoidal input-output curves of increasing gain toward the dendritic tip, as well as increased temporal summation (Figures 5D and 5E; see also Figures S4A–S4C). Analysis of the simulations revealed that the synaptic integration gradients can be explained by the interaction between active conductances and the progressive increase in dendritic input impedance toward the tip of the branch. Distal synapses generate a larger local dendritic depolarization due to the high local input impedance (Jack et al., 1975 and Nevian et al., 2007), which activates VGCCs and VGSCs, and relieves the magnesium block of NMDARs (Branco et al., 2010, Major et al., 2008, Mayer et al., 1984, Nowak et al., 1984, Schiller et al.