94 ± 0.1; not significantly different from 1, p = 0.54; peak EPSP at seven synapses = 97% ± 10% of linear sum; n = 5; Figures 2B and 2C). This shows that supralinear integration in layer 2/3 pyramidal cell dendrites crucially depends on NMDAR recruitment, which is facilitated ABT-888 purchase by activation of both VGCCs and VGSCs. We next investigated how unitary EPSPs varied with distance from the branch point. Analysis of somatic EPSPs evoked by single spine uncaging revealed no significant correlation between somatic peak amplitude and distance along the dendritic branch (r = 0.13; p = 0.12; n = 139 synapses from

18 dendrites; peak of distal EPSPs = 97% ± 3% of proximal EPSPs, not significantly different; p = 0.73; laser power, plane of focus, and spine Ibrutinib nmr size kept constant; Figures 2D, 2E, and S1C). However, block of NMDARs revealed a larger

NMDA component for EPSPs arising at more distal synapses (22% ± 4% for distal, 5% ± 7% for proximal; p = 0.041; n = 8), and lead to smaller somatic EPSPs for inputs at distal locations (82% ± 2% of proximal; p = 0.032), suggesting that NMDAR recruitment can partially compensate for dendritic filtering in these dendrites. Inputs to cortical neurons can exhibit different degrees of temporal synchrony (Abeles, 1991, König et al., 1996 and Shadlen and Newsome, 1995), and the efficacy of each particular input pattern depends on how well the individual inputs summate over time (Magee, 2000 and Rall, 1964). We therefore investigated how temporal summation varies along basal and apical oblique branches. We stimulated groups of seven synapses

at different dendritic locations using different interstimulus intervals and monitored the somatic EPSP peak. While for proximal synapses the EPSP peak decreased as input became more asynchronous, distal synapses produced EPSPs that had remarkably similar sizes over a range Parvulin of stimulation intervals (Figure 3A). Distal EPSPs at 10 ms intervals were 95% ± 1% of the peak at 1 ms intervals, while for proximal EPSPs the peak decreased to 56% ± 4% (p < 0.0001, ANOVA, n = 19; Figure 3B), which was also seen for small EPSPs (Figures S2E and S2F) and for a smaller number of stimulated synapses (Figure S1D). Between the branch point and the tip of the dendrite, temporal summation gradually increased by almost 2-fold (Figure 3C). This shows that in parallel with the changes in gain described above, single dendritic branches also have a gradient of efficacy for summation of asynchronous synaptic input. Layer 2/3 pyramidal cells lack a significant density of Ih channels (Larkum et al., 2007). In hippocampal CA1 pyramidal cells, the presence of a dendritic Ih gradient has been shown to normalize temporal summation over the dendritic tree (Magee, 2000).