Here, we detail how synaptic signaling exclusively from glutamate spillover engages neural circuits not previously predicted by anatomical mapping. First, we show that CF-mediated glutamate spillover affects the excitability of closely and distantly located MLIs. MLIs excited by spillover inhibit MLIs outside the spillover
limit, resulting in segregated activity based on proximity to the active CF. Single CF stimulation recruits AMPARs and NMDARs on MLIs within the spillover limit to trigger spiking and thus mediate a long-lasting component of spillover-mediated FFI to MLIs outside the spillover limit. Concerted activity of MLIs within and outside the spillover limit converges on neighboring PCs to generate a biphasic change in http://www.selleckchem.com/products/i-bet151-gsk1210151a.html inhibitory synaptic tone that initially decreases and subsequently increases evoked spike probability. These results demonstrate a pathway for information transfer in the cerebellar Cabozantinib mouse cortex that extends the influence of CFs beyond the conventional one-to-one relationship with postsynaptic PCs. Synaptic transmission
can be divided into fast and slow forms based on the kinetics of the postsynaptic response (Isaacson et al., 1993). Slow synaptic transmission is mediated by transmitters that act at diffusely distributed receptors located outside synapses (Fuxe and Agnati, 1991; but see Beckstead et al., 2004), whereas fast transmission is typically confined to synapses. In this view, spillover can Linifanib (ABT-869) be considered as an intermediate form of transmission, in which traditional fast neurotransmitters act at receptors distant from release sites. Spillover is not only associated with indirect modulation of fast transmission through G protein-coupled receptors (i.e., Isaacson et al., 1993; Scanziani et al., 1997; Mitchell and Silver, 2000), but also with direct signaling through activation of ionotropic receptors (i.e., Isaacson, 1999; DiGregorio
et al., 2002; Rancz et al., 2007; Scimemi et al., 2009). Direct spillover-mediated transmission improves efficacy and reliability of point-to-point transmission at some specialized synapses (DiGregorio et al., 2002; Sargent et al., 2005; Rancz et al., 2007) and has recently been implicated in the ability of synaptic inputs to generate nonlinear responses mediated by NMDARs (NMDA spikes; Chalifoux and Carter, 2011). In a few cases, synaptic signaling between neurons occurs solely via spillover in the absence of morphologically identified synaptic contacts (Isaacson, 1999; Szapiro and Barbour, 2007; Szmajda and Devries, 2011). Although there is debate about the prevalence of spillover at typical small glutamatergic synapses, our demonstration that spillover-mediated signaling recruits local microcircuits supports its functional significance.