Abstract
N-methyl-D-aspartate receptors (NMDARs) in cerebellar molecular layer interneurons (MLIs) are expressed and activated in unusual ways: at parallel fibre (PF) synapses they are only recruited by repetitive stimuli, suggesting an extrasynaptic location, whereas their activation by climbing fibre is purely mediated by spillover. NMDARs are thought to play an important role in plasticity at different levels of the cerebellar circuitry. Evaluation of the location, functional properties and physiological roles of NMDARs will be facilitated by knowledge of the NMDAR isoforms recruited. Here we show that MLI-NMDARs activated by both PF and climbing fibre inputs have similar kinetics and contain GluN2B but not GluN2A subunits. On the other hand, no evidence was found of functional NMDARs in the axons of MLIs. At the PF-Purkinje cell (PF-PC) synapse, the activation of GluN2A-containing NMDARs has been shown to be necessary for the induction of long-term depression (LTD). Our results therefore provide a clear distinction between the NMDARs located on MLIs and those involved in plasticity at PF-PC synapses.
Highlights
N-methyl-D-aspartate receptors (NMDARs) are normally composed of two copies of GluN1 and two of GluN2 subunits
Similar pharmacological profiles were obtained in experiments performed at room temperature with 4stimulation trains at 100 Hz. These results show that molecular layer interneurons (MLIs) NMDARs activated by parallel fibre (PF) inputs are sensitive to GluN2Bbut not to GluN2A-specific pharmacology
This would explain the variability observed, most likely due to an interplay between the antagonist and potentiating effects of Ro25-6981. All these currents were D-APV sensitive (0.02 ± 0.79 pA, n = 5 for the Zn2+ series; 0.92 ± 0.76 pA, n = 3 for the Ro25-6981 series). These results show that MLI NMDARs activated by climbing fibres (CFs) inputs present a variable degree of sensitivity to GluN2B-specific antagonist but are consistently insensitive to GluN2A-specific pharmacology
Summary
N-methyl-D-aspartate receptors (NMDARs) are normally composed of two copies of GluN1 and two of GluN2 subunits. GluN2 is coded by four different genes (GluN2A, 2B, 2C and 2D). The subunit composition defines the biophysical, pharmacological and signaling properties of NMDARs. In particular, during NMDAR-dependent spike timing-dependent plasticity, the receptor kinetics, endowed by the GluN2 subtypes, may participate in setting a time window for potentiation and depression (Markram et al, 1997; Bi and Poo, 1998; Sjöström et al, 2001). In situ hybridization studies have shown the expression of GluN1 and GluN2D subunits (Akazawa et al, 1994; Watanabe et al, 1994) and immunohistological studies reveal the expression of GluN1 and GluN2A/B subunits (with a non-segregating antibody; Petralia et al, 1994)
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