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

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 GTP?S 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.

SUBMITTER: Oshima-Takago T

PROVIDER: S-EPMC5541344 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Oshima-Takago Tomoko T Takago Hideki H

Open biology 20170701 7

<i>N</i>-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 ...[more]

PMID: 28747405

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Project description:Key pointsDuring development the giant, auditory calyx of Held forms a one-to-one connection with a principal neuron of the medial nucleus of the trapezoid body. While anatomical studies described that most of the target cells are temporarily contacted by multiple calyces, multi-calyceal innervation was only sporadically observed in in vivo recordings, suggesting a structure-function discrepancy. We correlated synaptic strength of inputs, identified in in vivo recordings, with post hoc labelling of the recorded neuron and synaptic terminals containing vesicular glutamate transporters (VGluT). During development only one input increased to the level of the calyx of Held synapse, and its strength correlated with the large VGluT cluster contacting the postsynaptic soma. As neither competing strong inputs nor multiple large VGluT clusters on a single cell were observed, our findings did not indicate a structure-function discrepancy.AbstractIn adult rodents, a principal neuron in the medial nucleus of the trapezoid (MNTB) is generally contacted by a single, giant axosomatic terminal called the calyx of Held. How this one-on-one relation is established is still unknown, but anatomical evidence suggests that during development principal neurons are innervated by multiple calyces, which may indicate calyceal competition. However, in vivo electrophysiological recordings from principal neurons indicated that only a single strong synaptic connection forms per cell. To test whether a mismatch exists between synaptic strength and terminal size, we compared the strength of synaptic inputs with the morphology of the synaptic terminals. In vivo whole-cell recordings of the MNTB neurons from newborn Wistar rats of either sex were made while stimulating their afferent axons, allowing us to identify multiple inputs. The strength of the strongest input increased to calyceal levels in a few days across cells, while the strength of the second strongest input was stable. The recorded cells were subsequently immunolabelled for vesicular glutamate transporters (VGluT) to reveal axosomatic terminals with structured-illumination microscopy. Synaptic strength of the strongest input was correlated with the contact area of the largest VGluT cluster at the soma (r = 0.8), and no indication of a mismatch between structure and strength was observed. Together, our data agree with a developmental scheme in which one input strengthens and becomes the calyx of Held, but not with multi-calyceal competition.

Dataset Information

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

Publications

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

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