In summary, we report that excitatory synaptic input from columnar and long-range intracortical circuits targeted to segregated sites within the electrically distributed dendritic tree of L5B pyramidal neurons can be integrated by the nonlinear interaction between axosomatic, apical dendritic trunk, and tuft integration compartments. Dendritic voltage-gated KV channels control this interaction. We suggest, therefore, that apical dendritic trunk and tuft KV channels operate as a tuneable gain control for interactive integration. As KV channels are regulated by neuromodulatory systems (Hoffman and Johnston, 1998, Hoffman and Johnston, 1999 and Nicoll

et al., 1990), apical dendritic KV channels may represent an important target for refining interactive integration in pyramidal neurons to guide behaviorally relevant Navitoclax research buy neuronal computations. Coronal brain slices containing the somatosensory Bortezomib price cortices were prepared from 4- to 7-week-old male Wistar rats following university and institutional guidelines using methods previously described (Williams, 2004 and Williams, 2005). Slices were submerged in artificial cerebrospinal fluid (aCSF) containing (in mM): 125 NaCl, 25 NaHCO3, 1.25 NaH2PO4, 3 KCl, 2 or 1.3 CaCl2, 1.0 MgCl2,

25 glucose, and 3 Na-pyruvate at 36°C –37°C. Dual and triple whole-cell recordings were made from thick-tufted L5B pyramidal neurons with BVC-700A (Dagan) amplifiers in “bridge” mode, and the electrode capacitance was carefully compensated. Somatic pipettes had open tip resistance of 3–6 MΩ and dendritic pipettes 10–12 MΩ, when filled with (in mM): 135 K-gluconate; 7 NaCl; 10 HEPES; 10 phosphocreatine; 2 Na2-ATP; 0.3 Na-GTP; 2 MgCl2 and 0.01 Alexa Fluor 568 or 594 (Molecular Probes) (pH 7.3–7.4; KOH). Neuronal

morphology was recorded by fluorescence microscopy (QImaging). Data were excluded if the nexus recording electrode was >50 μm from this site. The length of the apical dendritic Mephenoxalone trunk measured from structural images (soma intersection to nexus) was 749 ± 26 μm and diameter 2.8 ± 0.1 μm at 20 μm from the nexus (n = 13). The path length of tuft dendrites was 413 ± 14 μm and diameter between 0.8 and 2.3 μm (n = 40). Tuft recordings were discarded if series resistance was >60 MΩ. Simulated EPSCs were generated as ideal current sources (τrise and τdecay of 0.5 and 5 ms, respectively). Temporally uncorrelated barrages of simulated EPSCs were generated as trains of pseudorandomly occurring inputs (peak amplitude 0.1 nA) and injected at somatic and dendritic sites as previously described (Williams, 2005). Simulated EPSCs were therefore generated at somatic and dendritic sites as point current sources and not distributed conductances. Current and voltage signals were low pass filtered (DC to 10 kHz) and acquired at 30–50 kHz. Data were acquired and analyzed using AxographX software (AxographX). All drugs were dissolved in the recording aCSF and applied by bath perfusion.