Role of presynaptic kainate receptors at parallel fiber-purkinje cell synapses in induction of cerebellar LTD: interplay with climbing fiber input.

Until recently, except for A1 adenosine, N-methyl-d-aspartate, and cannabinoid receptors, little effort has been made to unravel possible roles of parallel fiber (PF) presynaptic receptors in long-term depression (LTD) of synaptic transmission at PF-Purkinje cell (PC) synapses. Presynaptic kainate (KA) receptors are also present on PFs and might also influence LTD induction by modulating glutamate (Glu) release at PF-PC synapses. This hypothesis was tested by comparing the efficacy of two pairing protocols in inducing LTD in adult wild-type and knock-out mice for the Glu receptor 6 (GluR6) subunit of KA receptors. Activation of presynaptic KA receptors was unnecessary for LTD induction when PF inputs were paired with climbing fiber (CF) stimulation but became crucial when CF input was replaced by direct depolarization of PCs. By comparing basal paired-pulse facilitation of PF-excitatory postsynaptic currents (EPSCs) and depolarization-induced suppression of excitation in adult wild-type and GluR6 knock-out mice, it was shown that the participation of PF presynaptic KA receptors in LTD induction was likely to mainly result from their tonic activation by basal extracellular Glu, rather than from their activation by retrograde release of Glu by PCs during pairing protocols. Finally, this study suggests that, in adult mice, CFs not only participate in LTD induction by depolarizing postsynaptic cells but also by activating postsynaptic mGluR1alpha metabotropic glutamate receptors at CF-PC synapses.