We next tested whether the kinetics of somatic current injections

We next tested whether the kinetics of somatic current injections can affect the CpS waveform. By adjusting the amplitude of the somatic current injection (range: 5–18 nA), we triggered

complex-like spikes that closely resembled synaptically stimulated CpSs (Figure 7; McKay et al., 2005 and Davie et al., 2008). First, we injected a current (Ifast; Figure 7A; 0.4 ms rise and 4 ms decay) that triggered a complex-like spike with the maximal number of spikelets without inactivation that occurs with increasing current injection ( Davie et al., 2008). Repetitive 2 Hz injection of Ifast did not alter any parameter of complex-like spikes, suggesting that 2 Hz stimulation does not alter learn more CpSs simply by inactivation of voltage-gated conductances ( Figure S4). We

then reduced the amplitude of the injected current by 20% without altering the kinetics (Ifast-20%Q ; Figure 7A). This value matches the reduction of the current-time integral that occurs with 2 Hz synaptic stimulation ( Figure 1; charge is reduced by 20.4 ± 2.6%). Decreasing the amplitude (and charge) by 20% did not alter the number of spikelets ( Figure 7B; n = 6; p > 0.05; ANOVA), although there was a slight reduction in the amplitude of the first spikelet ( Figures 7C and 7D; n = 6). With further reduction of the somatically injected charge (30% of Ifast) CFTR modulator the number of spikelets decreased ( Figure S5; n = 6; p < 0.05; ANOVA). Finally, we imposed the same charge as Ifast-20%Q but with altered kinetics by decreasing the injected current peak amplitude and slowing the decay time to 5 ms. The resulting current waveform (Islow-20%Q; Figure 7A) had a peak amplitude and a current-time integral that was reduced by 36% and 20%, respectively, compared to Ifast. The number of spikelets evoked by Islow-20%Q was reduced compared to those evoked by Ifast ( Figure 7B; 2.8 ± 0.17 and 4.2 ±

0.3; n = 6; p < 0.05; ANOVA). This suggests that the quantity of somatic charge is not the sole determinant of the number of spikelets until and that the kinetics of the injected current can regulate the shape of the complex-like spike waveform. Remarkably, the Islow-20%Q waveform altered the spike height, rising rate, and ISI of the complex-like spike response in the same manner as 2 Hz synaptic stimulation affected the CpS (compare Figures 6C–6E and 7C–7E). For the second and third spikelet, the increase in spike height (69.3 ± 23.5% and 166.5 ± 68.0%; n = 6 and 5; p < 0.05; ANOVA), rate of rise (80.4 ± 43.1% and 101.9 ± 37.8%; n = 6 and 5; p < 0.05; ANOVA), and ISI (22.2 ± 7.7% and 30.8 ± 10.1%; n = 6 and 5; p < 0.05; ANOVA) caused by Islow-20%Q is predicted to increase the reliability of spikelet propagation. The decrease in the first spikelet height (−18.8 ± 2.4%; n = 6; p < 0.

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