, 2010) (Figure 3). Interestingly, while facilitation was prevented by philantotoxin (a blocker of Ca2+-permeable receptors), the inhibitory effect

involved PLC. Thus, the net result of activating presynaptic KARs by endogenous glutamate may depend on the glutamate concentration actually reaching the presynaptic KARs, which will ultimately depend on the magnitude of glutamate spillover arising from different patterns of synaptic activity coupled to the astrocyte uptake capacity. This hypothesis is further substantiated by data from the cerebellum, where bidirectional modulation of transmitter release has also been found. Synaptically activated buy SAR405838 presynaptic KARs facilitate and GSK2118436 datasheet depress transmission at parallel

fiber synapses (Delaney and Jahr, 2002). Activation of presynaptic KARs by synaptically released glutamate at parallel fibers facilitates glutamate release to both interneurons (e.g., stellate or basket cells) and Purkinje cells when these fibers are subjected to a regime of low-frequency stimulation. By contrast, with high-frequency stimulation, the synapses onto inhibitory interneurons are depressed, while synapses at Purkinje cells are still facilitated. Such differential sensitivities to the frequency of these two synapses may regulate the excitation/inhibition balance of Purkinje cells and, therefore, cerebellar output. Thus, at some structures,

KARs bestow computational properties to circuits according to the activity regime of afferent inputs. Presynaptic regulation of excitatory transmission by KARs has been studied extensively at MF-CA3 synapses. At these synapses, presynaptic KARs are implicated in the characteristic frequency-dependent facilitation of MF excitatory transmission (Schmitz et al., 2001, Lauri et al., 2001, Contractor et al., 2001 and Pinheiro et al., 2007), a phenomenon initially ascribed to the residual intraterminal calcium. Since KAR antagonists attenuate the potentiation of the second EPSC during high-frequency trains (e.g., 25 Hz; Schmitz et al., 2001), the synaptic activation of presynaptic KARs must be quite fast (10–30 ms), indicating that KARs should be found near the active zone. Indirect evidence suggests that the facilitation almost of glutamate release may occur through the depolarization of presynaptic terminals (Schmitz et al., 2001) that should enhance action potential-driven Ca2+ influx (Kamiya et al., 2002 and Lauri et al., 2003). The reduction of synaptic facilitation by a blocker of Ca2+-permeable KARs (Lauri et al., 2003) also points to a contribution of direct Ca2+ entry through these receptor channels, although Ca2+ mobilization from intracellular stores may also add to this use-dependent facilitation of glutamate release (Lauri et al., 2003 and Scott et al., 2008).