, 2012). The inhibition of glutamate release EX 527 cost at Schaffer collaterals-CA1 synapses does not involve protein kinases but, rather, a membrane-delimited action that probably involves the direct inhibition of presynaptic Ca2+ channels by G protein γβ subunits (De Waard et al., 1997). The inhibitory

effects of KARs upon tonic activation by endogenous glutamate at these two hippocampal synaptic populations have been observed during development and involve KAR metabotropic signaling (Lauri et al., 2005, Lauri et al., 2006 and Sallert et al., 2007). Tonic activation of presynaptic KARs in the adult brain also inhibits glutamate release in the rat globus pallidus, once again mediated by a presynaptic Gi/o-protein-coupled and PKC-dependent mechanism (Jin and Smith, 2007). What now seems clear is that presynaptic KARs modulate transmitter release in a bidirectional manner: facilitation probably occurs through their ionotropic activity, while inhibition seems to involve noncanonical metabotropic signaling. It is possible that the threshold to activate one or other KAR signaling pathways would determine physiological responses. In summary, the presynaptic

modulation of both glutamate and GABA release together with the postsynaptic regulation of neuronal excitability clearly demonstrates that KARs are endowed with diverse capacities. These activities enable them to fine-tune synaptic function and regulate neuronal network activity in the adult brain, bestowing them with 3-deazaneplanocin A manufacturer a much broader role at synapses than the simple transfer of information. KARs are expressed strongly in the brain during development in a complex cell-type-specific manner. The properties of synapses during development

differ significantly from those at mature stages and it is now known that presynaptic KARs contribute to these changes. The expression of KARs, and particularly of GluK1 subunits, increases markedly and peaks during the first week of life in rodents (Bahn et al., 1994). In immature hippocampal CA1 synapses, the tonic activation of KARs by ambient glutamate keeps the probability of release low (Lauri et al., 2006). However, a burst of synaptic activity produces strongly facilitating postsynaptic responses, a facilitation that is not only abolished in the presence of a KAR antagonist nearly but also later in development. Interestingly, this change is recapitulated by inducing LTP and it seems that the tonic stimulation of KARs by ambient glutamate is no longer possible under each of these circumstances, changing the short-term synaptic dynamics. It is possible that the lower ambient glutamate contributes to the lack of tonic KAR activation after the first postnatal week. However, it does seem that the affinity of the receptor actually changes, making it less sensitive to the agonist. Indeed, it has been claimed that a change in an isoform of the GluK1 subunit in KARs is responsible for this lower affinity (Vesikansa et al., 2012).