, 2002) and which is present close to olivary Connexin 36 plaques in the inferior olive (Alev et al., 2008). We therefore repeated the plasticity experiments with KN62, a selective CaMKII inhibitor (Tokumitsu et al., 1990), in the pipette solution (10 μM). No significant plasticity was observed under these conditions (coupling after induction 89% ± 29% of baseline; n = 4 pairs, p = 0.70; Figures S4C and S4D). Since complex GS-7340 clinical trial spike synchrony depends on both synaptic input and electrotonic coupling between olivary neurons (Marshall et al., 2007 and Wise et al., 2010), it is important to know how the strength
of chemical synapses is affected by protocols that modify gap junctional coupling. To test this, we assessed the chemical synaptic response (i.e., the evoked EPSP) along with electrical coupling strength. During the baseline and monitoring periods, we used a stimulus strength that would allow direct monitoring of the EPSP (without occlusion of the EPSP by olivary bursts). The induction protocol consisted of a steady-state depolarization 3-Methyladenine nmr (0–500 pA), with 100 synaptic stimuli at 1 Hz. The synaptic stimuli were paired with short depolarizing pulses (20 ms, 800 pA) to ensure reliable induction of burst spiking (Chorev et al.,
2007 and Khosrovani et al., 2007). As before, we found that the electrical coupling was depressed after induction (coupling reduced by 37% ± 7.5% of baseline, p < 0.01; n = 11 pairs; Figure 4). Since the EPSP was occasionally occluded by the low-threshold calcium spike or a rebound spike, our analysis was restricted to subthreshold synaptic responses (mean baseline EPSP size 6.4 ± 0.3 mV; n = 14 cells). We found that the strength of the chemical synapse in these cells did not vary significantly after induction (107% ± 7.8% of baseline; mean EPSP size after induction 6.1 ±
0.8 mV, p = 0.39, n = 17 cells). This indicates that plasticity induction is specific to electrical synapses Thalidomide and does not affect chemical synapses in the same cell, even though the chemical synapses have been used to induce the plasticity. We have demonstrated that physiological activation of glutamatergic synapses triggers long-term depression of electrical coupling between inferior olive neurons while maintaining the strength of the chemical synapse. This provides a direct functional role for the precise anatomical arrangement of glutamatergic synaptic input and gap junction plaques in the synapse at the glomerulus that links multiple dendritic spines. The fact that chemical-electrical synapses have been shown to coexist throughout the mammalian nervous system, and the demonstration of similar intersynaptic plasticity mechanisms in the Mauthner cell of the goldfish (Yang et al., 1990, Pereda and Faber, 1996, Pereda et al.