0 ± 4.7%; n = 6; p < 0.05; ANOVA) is unlikely to affect propagation because it is already highly reliable ( Khaliq

and Raman, 2005 and Monsivais et al., 2005). Thus, although there are fewer spikelets with the injection of Islow-20%Q or by 2 Hz synaptic stimulation, each spikelet is likely to have a greater chance for propagation. To directly determine whether increased activity and accompanying changes in the CpS waveform affect axonal propagation of spikelets, we stimulated CFs and ABT-888 mouse recorded simultaneously from the soma and axon (Figure 8A). The axonal recording sites were approximately 200 μm from the soma, which is distal to the spike initiation site (Clark et al., 2005). Consistent with Selleckchem GDC-0068 the measures from somatic CpSs, the first spike successfully propagated regardless of the stimulation frequency. Increasing the stimulation frequency from 0.05 to 2 Hz resulted in fewer somatic spikes that were, on average, more efficiently propagated down to the axonal recording site. After determining whether somatic spikelets successfully propagated to the axonal recording site (see Experimental Procedures), we calculated the cumulative propagation probability of “x” number of spikelets regardless of position within the CpS. In recordings shown in Figure 8B, the cumulative probability of having at least two or three spikes successfully propagate

down the axon is 0.5 and 0, respectively, although the somatic recording always has three spikelets. At 2 Hz, the cumulative probability of at least two spikelets propagating increases to 1, equal to the propagation probability for one spikelet and matching the number of somatic spikelets. On average, the propagation probability of at least two and at least three spikelets increased from 0.61 ± 0.1 and 0.24 ± 0.06 at 0.05 Hz to 0.87 ± 0.05 and 0.52 ± 0.14 at 2 Hz, respectively (Figure 8C; n = 10 dual somatic and axonal recordings;

p < 0.05). Thus we conclude that desynchronization of MVR enhances the information transfer by CpSs. We show that stimulation others of CFs across physiological frequencies results in desynchronization of vesicle fusion as summarized in Figure 9. Synchronized univesicular release (UVR; Figure 9A1) results in a low synaptic glutamate concentration transient (Figure 9B1) that likely mediates CpSs that resemble simple spikes (Figure 9C1). Multivesicular release (MVR; Figure 9A2) leads to a high synaptic glutamate concentration that is prolonged (Figure 9B2) and CpSs with several spikelets on top of an afterdepolarization (Figure 9C2). Increased activity desynchronizes MVR (desync. MVR; Figure 9A3) with reduced but prolonged synaptic glutamate transients (Figure 9B3) that decrease the number of spikelets within each CpS (Figure 9C3) but enhances axonal propagation. This desynchronization disrupts the timing of MVR at individual active zones and occurs concomitantly with vesicle depletion.