In this case, the cell does not monitor dendritic excitability, suggesting a sensor that is localized near the soma. A good candidate for the messenger would be Ca2+ influx during AP repolarization, which displays a relatively constant amplitude and duration in the soma compared with dendrites. Alternatively, because of their location distant from the nucleus, dendritic channels and receptors may simply PD173074 be untethered from strict homeostatic excitability mechanisms.

In any event, it is surprising that dendritic excitability is not more closely regulated. Dendritic voltage-gated ion channels regulate the processing and storage of incoming information in CA1 pyramidal neurons (Shah et al., 2010). Perhaps the dynamic nature of channel properties and expression during normal function in dendrites prohibits the establishment of a set point state of excitability. We should make the distinction that the applicable data come only

SB203580 order from recordings in CA1 primary apical dendrites. Oblique dendrites may well use mechanisms to homeostatically regulate their excitability. In CA1 neurons, AP back-propagation decreases with activity (Spruston et al., 1995) because of a combination of slow recovery from inactivation for dendritic Na+ channels and the activity of A- type K+ channels (Colbert et al., 1997 and Jung et al., 1997). We found DPP6 to be particularly important in the regulation of back-propagation at lower frequencies (Figures Ketanserin 5B and 5C). An explanation would be that normally a certain fraction of A-type K+ channels are able to recover from inactivation in between APs, but that without DPP6 the remaining A-type channels are too slow to recover from inactivation, allowing greater back-propagation. DPP6 therefore may be an important contributor to the cellular- and circuit-level mechanisms of theta rhythm (5–10 Hz) found in EEG recordings of the hippocampus during exploratory behavior and REM in the hippocampus. In addition to enhanced back-propagation, we observed that Ca2+

spikes were more readily generated in DPP6-KO dendrites. The activation of dendritic voltage-gated Ca2+ channels by back-propagating APs results at a “critical” frequency will induce a burst of mixed Ca2+ and Na+ action potentials in CA1 pyramidal neurons. Dendritic voltage-gated K+ channels modulate this change in AP firing mode from single to burst firing (Golding et al., 1999 and Magee and Carruth, 1999). We found that the critical frequency for Ca2+ electrogenesis in WT neurons of ∼130 Hz was dramatically lowered to only 85 Hz in DPP6-KO neurons. We have observed previously that this type of complex firing is critical for the induction of GluA1-independent LTP of synaptic inputs using a theta burst-pairing protocol (Hoffman et al., 2002). Using a similar protocol, it has been shown that Kv4.2-KO mice have a lower threshold for LTP induction than WT (Chen et al., 2006 and Zhao et al., 2010).