However, although the basic anatomical, electrophysiological, and synaptic properties of rodent CA3 pyramidal cells have been characterized (e.g., Amaral and Witter, 1989, Li et al., 1994, Miles and Wong, 1986, Spruston et al., 1995 and Urban and Barrionuevo, 1998), exploration selleckchem of dendritic integration and plasticity has only recently begun (Kim et al., 2012). Here we set out to study the impact of active dendritic integration on the processing of correlated synaptic input such as that generated by ensemble activity in the CA3 circuitry. To investigate dendritic integration of CA3 pyramidal neurons, we used two-photon glutamate

uncaging at multiple synapses on thin dendritic segments in the basal (stratum oriens) and proximal apical (stratum radiatum) arborization (synapses here are primarily CA3 associational/recurrent; DNA Damage inhibitor Amaral and Witter, 1989 and Li et al., 1994) and compared the peak amplitude of the measured voltage responses to the arithmetic sum of the individual inputs (expected amplitude; Losonczy and Magee, 2006). Stimulating an increasing number of synapses with a high degree of synchrony (i.e., up to 20–40 inputs within a maximum of 6–12 ms, see Experimental Procedures and Supplemental Experimental Procedures available online) evoked depolarizations that were much larger than the expected sum in the vast majority of the dendrites (Figure 1). The deviation from linear integration progressively increased

as input numbers were increased and reached a steady-state level (nonlinearity: 5.35 ± 0.43 mV additional depolarization, ∼50%–100% increase; n = 57 dendrites in 42 cells; Figures 1D and 1E) at a similar input range in all neurons (5–8 mV expected amplitude). The additional depolarization produced by nonlinear dendritic integration was largest in the apical dendrites (apical: 8.16 ± 1.45 mV, n = 9; basal: 4.83 ± 0.40 mV, n = 48; p < 0.05, Mann-Whitney test). The majority of the supralinear voltage response was generated by a slow component, although in many basal dendrites small amplitude fast spikelets were

also observed (Figure 1B). To dissect the underlying mechanism of the nonlinear component of dendritic from integration, we first characterized the fast spikelet that was characteristic of a local Na+ spike (Ariav et al., 2003, Losonczy and Magee, 2006, Losonczy et al., 2008 and Kim et al., 2012). The fast spikelet was indeed eliminated by 0.5–1 μM tetrodotoxin (TTX; n = 7; Figure S1A), confirming that it was mediated by voltage-gated Na+ channels (VGSCs). Determination of the somatic strength of dendritic Na+ spikes (by the rate of rise; dV/dt) generated in various regions of the arbor revealed a striking difference between apical and basal oblique dendrites (Figure 2A). While a fast spikelet could be observed in most basal dendrites (84.8%), similar stimulation generated Na+ spikes that were detectable at the soma in only a minority (29.4%) of apical dendrites, with a small average strength (0.65 ± 0.25 V/s, n = 10).