Frequency-dependent

AP back-propagation is functionally c

Frequency-dependent

AP back-propagation is functionally critical in the generation of Ca2+ spikes and burst firing in pyramidal neurons (Larkum et al., 1999). The “critical frequency” is the frequency of bAP trains where a dendritic Ca2+ spike is induced. Here, critical frequency was measured using dual whole-cell current-clamp recordings from the soma and apical dendrites in CA1 WT and DPP6-KO neurons by inducing trains of five APs with somatic current injection at frequencies ranging from 20–200 Hz (Figure 6A). WT dendrites had a critical frequency of 127.8 ± 4.9 Hz (Figures 6B–6D, n = 9). DPP6-KO dendrites were significantly more excitable with an average critical frequency of 85.0 ± 5.7 Hz (Figures 6B–6D, n = 8, p < 0.05). We have observed previously that this type of complex firing is critical for the induction RG7420 clinical trial of LTP using a theta burst-pairing protocol (Hoffman et al., 2002). Using a similar protocol (Figure 7A), we found that the spike-timing window for LTP induction is extended in recordings from DPP6-KO CA1 neurons compared with WT (Figures 7B–7E). A theta burst protocol,

consisting of two APs delivered 31–35 ms after synaptic stimulation to induce Everolimus 5 EPSPs at 100 Hz, led to LTP in both WT and DPP6-KO recordings (Figures 7B and 7E). When the APs were delivered 41–45 ms after the onset of synaptic stimulation, however, synaptic potentiation was only observed in DPP6-KO recordings (Figures Cell 7D and 7E). APs delayed >46 ms relative to synaptic stimulation failed to induce LTP in either group (Figure 7E). We found that LTP induction in both WT and DPP6-KO recordings was coincident with

enhanced depolarization via putative Ca2+ spikes, supporting the notion that burst firing enhances LTP induction (Figures 7F and 7G). Despite the considerable effect on dendritic excitability and synaptic plasticity, elimination of DPP6 had only minor affects on firing behavior evoked by somatic current into CA1 neurons (Figures 8A–8E). No change was observed for the number of APs evoked by a 200 pA current injection (Figure 8C), first AP onset time (Figure 8D), or threshold potential in CA1 pyramidal neurons (Figure 8E). However, compared with WT, we did find a significant difference in the AHP in DPP6-KO (Figure 8F). The enhanced AHP in DPP6-KO recordings may be caused by slower A-current inactivation during repolarization (Figures 4G and 4H). These relatively minor changes in excitability measured in the soma compared with that found in dendrites are reminiscent of those found for CA1 pyramidal cells after genetic loss of Kv4.2. However, in Kv4.2-KO mice, this was caused by an upregulation of non-Kv4 subunits, most likely Kv1 family members, in the somatic region of CA1 neurons along with increased GABAergic conductances (Andrásfalvy et al., 2008 and Chen et al., 2006).

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