In these experiments, the amplitude of dendritic bAPs also remained unaltered during the train (Figure 1L). In addition, we never observed signs of dendritic regenerative potentials during bursts of action potentials, indicating a relatively low density of voltage-gated channels recruited by trains of bAPs. The strong attenuation of bAPs during invasion into granule cell dendrites raises the question if the associated Ca2+ transients Dolutegravir also show a distance-dependent attenuation. Using multiphoton Ca2+ imaging, we found that Ca2+ transients associated with single bAPs showed little attenuation in the first, larger caliber dendrite segments up to approximately 50 μm from the

soma (Figure 1M). Subsequently, however, attenuation was substantial toward more distal sites (Figures 1M and 1N, decrease for distances >50 μm from the soma 35.5% ± 0.4%/100 μm, 124 linescans,

n = 14 cells). Similar attenuation was observed for action potential bursts elicited by brief current injections (5 APs at 20 Hz, n = 3, 26 linescans, see Figure S1D available online). This is markedly different from pyramidal basal INCB024360 in vivo dendrites, in which no appreciable attenuation of bAP-associated Ca2+ transients is observed even when bAP amplitudes are markedly attenuated. The dendritic back-propagation of action potentials in pyramidal neurons is substantially modulated by voltage-gated Na+ channels (Colbert et al., 1997, Jung et al., 1997, Spruston et al., 1995, Stuart et al., 1997b and Stuart and Sakmann, 1994). Because the dendritic recordings so far suggested a comparatively low Parvulin density of Na+ currents in granule cell dendrites, we examined whether dendritic Na+ channels affect AP back-propagation in dentate granule cells by locally applying the Na+

channel blocker tetrodotoxin to granule cell dendrites during dual somatodendritic recordings (TTX, 1 μM, n = 4, average distance of application site from soma 167.9 ± 13.8 μm, Figures 2A–2D). During continuous local application of TTX, the somatic AP was initially unaffected, but bAP amplitudes decreased (red symbols in Figure 2B, see example traces at time point 2). Twenty seconds after onset of TTX application, the dendritic to somatic amplitude ratio was reduced by 12.6% ± 8.9% (n = 4). Ultimately, TTX application caused failure of somatic action potentials in all experiments (example traces at time point 3 in Figure 2B), indicating TTX had reached the perisomatic region including the axon initial segment. Just before the somatic action potential failed, the dendritic to somatic AP amplitude ratio was reduced by 42.7% ± 10.2% (summary in Figure 2C). Because the recruitment of voltage-gated Na+ currents is dependent on the membrane potential, which may be more depolarized in vivo, we also examined action potential back-propagation over a range of membrane potentials.