, 2008 and Noor et al., 2010)

and amyotrophic lateral sclerosis susceptibility gene (Cronin et al., 2008 and van Es et al., 2008). DPP6 enhances the opening probability and single-channel conductance of Kv4 channels and increases channel surface expression in heterologous systems (Kaulin et al., 2009, Maffie and Rudy, 2008 and Nadal OSI-744 datasheet et al., 2003). A ternary complex of Kv4, DPP6, and Kv channel-interacting proteins (KChIPs) is thought to underlie the native A-type K+ current in CA1 neurons (Kim and Hoffman, 2008 and Maffie and Rudy, 2008). To investigate the influence of DPP6 in a native system, we generated conditional DPP6 knockout (DPP6-KO) mice (DPP6fl/fl). These mice were crossed to a Cre deleter strain expressing Cre recombinase in the germline to generate DPP6 null alleles (DPP6-KO mice). In patch clamp recordings from wild-type (WT) mouse CA1 hippocampal dendrites, we observed that the density of A-type currents increased with distance from the soma, as found previously for rats (Hoffman et al., 1997). However, in dendritic recordings from DPP6-KO mice, the A-current distribution in CA1 primary apical dendrites was altered so

that the density was, on average, the same throughout the primary apical dendrite. Accordingly, dendritic excitability was enhanced in CA1 dendrites from acute hippocampal MK-1775 clinical trial slices prepared from adult DPP6-KO mice: bAPs were better able to invade distal dendrites, trains of APs were more faithfully conveyed than in recordings from WT mice, and the threshold frequency for the generation of Ca2+ spikes and long-term potentiation (LTP) was lowered in DPP6-KO dendrites. In contrast to the critical role of DPP6 in dendritic excitability, firing behavior evoked by somatic heptaminol current injections was only minorly affected in DPP6-KO CA1 recordings. In addition to establishing a role for DPP6 in generating the A-current gradient in CA1 neurons, these observations provide evidence that the enhanced dendritic A-current is particularly important for the regulation of dendritic

excitability including dendritic spiking and plasticity. We have previously shown using siRNA that acute knockdown of DPP6 moderately influences the firing patterns of hippocampal CA1 neurons in somatic recordings from hippocampal organotypic slice cultures (Kim et al., 2008). However, it is at the distal apical dendrites of CA1 neurons that A-current expression and activation prominently control excitability, and the small caliber of dendrites in cultured neurons precludes electrophysiological recordings from distal sites. Therefore, to investigate the functional significance of DPP6 in mature dendrites, we generated DPP6-KO mice (Figure 1A). DPP6-KO mice displayed a total loss of DPP6 mRNA and protein (Figures 1B–1D). The closely related family member DPP10 is not normally expressed in CA1 pyramidal dendrites (Zagha et al., 2005) and is not upregulated in these cells in DPP6-KO mice (Figure 1E).