NMDA receptor-dependent presynaptic inhibition at the calyx of Held synapse of rat pups.

Tomoko Oshima-Takago,Hideki Takago

doi:10.1098/rsob.170032

Abstract

N-Methyl-d-aspartate receptors (NMDARs) play diverse roles in synaptic transmission, synaptic plasticity, neuronal development and neurological diseases. In addition to their postsynaptic expression, NMDARs are also expressed in presynaptic terminals at some central synapses, and their activation modulates transmitter release. However, the regulatory mechanisms of NMDAR-dependent synaptic transmission remain largely unknown. In the present study, we demonstrated that activation of NMDARs in a nerve terminal at a central glutamatergic synapse inhibits presynaptic Ca2+ currents (ICa) in a GluN2C/2D subunit-dependent manner, thereby decreasing nerve-evoked excitatory postsynaptic currents. Neither presynaptically loaded fast Ca2+ chelator BAPTA nor non-hydrolysable GTP analogue GTPγS affected NMDAR-mediated ICa inhibition. In the presence of a glutamate uptake blocker, the decline in ICa amplitude evoked by repetitive depolarizing pulses at 20 Hz was attenuated by an NMDAR competitive antagonist, suggesting that endogenous glutamate has a potential to activate presynaptic NMDARs. Moreover, NMDA-induced inward currents at a negative holding potential (−80 mV) were abolished by intra-terminal loading of the NMDAR open channel blocker MK-801, indicating functional expression of presynaptic NMDARs. We conclude that presynaptic NMDARs can attenuate glutamate release by inhibiting voltage-gated Ca2+ channels at a relay synapse in the immature rat auditory brainstem.

Highlights

The N-methyl-D-aspartate receptor (NMDAR), a member of the ionotropic glutamate receptor family, consists of glycine-binding GluN1 subunits together with glutamate-binding GluN2 (GluN2A –D, formerly NR2A –D) subunits and/or glycine-binding GluN3 (GluN3A,B, formerly NR3A,B) subunits, which form a heteromeric receptor complex [1,2]
NMDARs are relevant to nitric oxide synthesis in the cerebellum [54,55] as well as protein kinase C activation in the neocortex [56], we examined whether such chemicals as the nitric oxide synthase inhibitor L-NNA (1 mM) or the protein kinase C inhibitor staurosporine (2 mM) attenuate inhibits presynaptic Ca2þ currents (ICa) inhibition induced by NMDA (500 mM)
We demonstrated that activation of GluN2C/2D subunit-containing presynaptic NMDARs inhibits voltage-gated Ca2þ channels (VGCCs), thereby attenuating action potential-driven release at a central glutamatergic synapse of young rats

Summary

Introduction

The N-methyl-D-aspartate receptor (NMDAR), a member of the ionotropic glutamate receptor family, consists of glycine-binding GluN1 (formerly NR1) subunits together with glutamate-binding GluN2 (GluN2A –D, formerly NR2A –D) subunits and/or glycine-binding GluN3 (GluN3A,B, formerly NR3A,B) subunits, which form a heteromeric receptor complex [1,2]. Activation of presynaptic NMDARs enhances spontaneous release at glutamatergic synapses in the cerebral cortex [10,21,22,23], hippocampus [14,24] and amygdala [25] as well as at GABAergic synapses in the cerebellum [18,26 –30] and hippocampus [31]. Presynaptic NMDAR activation facilitates action potential-evoked glutamate release at cortical [21,22] and hippocampal [32] synapses, and induces long-term potentiation at glutamatergic synapses in the amygdala [33] and subiculum [34,35].

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