Subsequently, it has been established that high-affinity NMDARs are a common target for spillover-mediated signaling (i.e., Asztely et al., 1997; Isaacson, 1999; Overstreet

et al., 1999; Carter and Regehr, 2000; Scimemi et al., 2004). At PF-MLI synapses, NMDAR activation is only detected during high-frequency or high-intensity IOX1 datasheet molecular layer stimulation, indicating that NMDARs are located outside the postsynaptic density (Carter and Regehr, 2000; Clark and Cull-Candy, 2002). Such stimulation protocols produce synchronous activation of a high density of local fibers, generating extrasynaptic signaling that may be rare in vivo during physiological stimuli (Arnth-Jensen et al., 2002; Marcaggi and Attwell, 2005). We found that spillover from a single CF generates both AMPAR- and NMDAR-mediated depolarization of MLIs, suggesting that CF and PF stimulation activates different sets of receptors. In contrast to FFI mediated by PFs (Figure S3 and Mittmann et al.,

2005), CF stimulation generates a long-lasting (∼100 ms) component of inhibition to MLIs that contributes to the long-lasting buy PD-0332991 component of disinhibition to PCs (Figure 7). The persistent NMDAR-mediated component thus expands both inhibition and disinhibition to PCs, potentially enhancing the contrast between areas of active and inactive PCs. Typical FFI narrows the window for synaptic integration by providing a rapid increase in principal cell inhibition either that provides balanced regulation of excitation (Pouille and Scanziani, 2001; Wehr and Zador, 2003; Mittmann et al., 2005; House et al., 2011). Thus, we were surprised that blocking GABAARs had only small, variable effects on the number of CF-evoked

APs in individual MLIs (Figure 4). We considered three potential factors that could produce variability in the effectiveness of CF-FFI, including the magnitude of FFI, the location of FFI relative to CF-mediated excitation, and the potential for a fraction of MLI inputs to promote MLI excitability (Chavas and Marty, 2003). Since CF-mediated inhibition of PF-evoked spiking was robust (Figure S6) and somatic inhibitory conductance injection effectively decreased CF excitation of MLIs, we predict that the locations of excitatory and inhibitory conductances could promote the transmission of somatic CF-mediated excitation (Brown et al., 2012) despite reciprocal inhibition. Although MLIs are generally thought to be electronically compact because of their high input resistance and short dendrites, their thin dendrites behave as passive cables that filter synaptic responses, resulting in sublinear integration (Abrahamsson et al., 2012). This suggests that shunting that depends on location (i.e., Gulledge and Stuart, 2003) may be important for MLI inhibition.

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