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The Journal of Neuroscience, September 12, 2007, 27(37):9989-9999; doi:10.1523/JNEUROSCI.2506-07.2007

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Cellular/Molecular
Coincident Activation of Metabotropic Glutamate Receptors and NMDA Receptors (NMDARs) Downregulates Perisynaptic/Extrasynaptic NMDARs and Enhances High-Fidelity Neurotransmission at the Developing Calyx of Held Synapse

Indu Joshi, ^* Yi-Mei Yang, ^* and Lu-Yang Wang

The Program for Neurosciences and Mental Health and Division of Neurology, The Hospital for Sick Children, and Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1X8

Correspondence should be addressed to Dr. Lu-Yang Wang, Division of Neurology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Email: luyang.wang{at}utoronto.ca

NMDA receptors (NMDARs) are usually downregulated in developing central synapses, but underlying mechanisms and functional consequences are not well established. Using developing calyx of Held synapses in the mouse auditory brainstem, we show here that pairing presynaptic stimulation with postsynaptic depolarization results in a persistent downregulation in the summated amplitude of NMDAR-mediated EPSCs (NMDAR-EPSCs) during a train of stimuli (100/200 Hz, 100 ms) at both 22°C and 35°C. In contrast, the amplitude of single NMDAR-EPSCs or AMPA receptor-mediated EPSCs in the same synapses is not significantly altered, implying a preferential downregulation of perisynaptic/extrasynaptic NMDARs. Induction of this downregulation is blocked by antagonists for NMDARs or group I metabotropic glutamate receptors (mGluRs), suggesting that coincident activation of these two receptors is required. When the postsynaptic neuron is loaded with the fast Ca²⁺ buffer BAPTA or depolarized to +60 mV to reduce the driving force for Ca²⁺ influx, downregulation of the summated NMDAR-EPSCs is abolished, indicating Ca²⁺ plays a critical role in the induction. The expression of this downregulation depends on ongoing synaptic activity, and is attenuated by a dynamin peptide (D15) that blocks clathrin-dependent internalization. We further demonstrated that the same induction paradigm specifically reduces NMDAR-dependent plateau potential and aberrant spike firings during repetitive activity. Together, our results suggest that coincident activation of mGluRs and NMDARs during intense synaptic activity may lead to selective endocytosis of NMDARs in the perisynaptic/extrasynaptic domain, and implicate that mGluRs are potentially important for gating development of high-fidelity neurotransmission at this synapse.

Key words: calyx of Held-MNTB synapse; mGluRs; NMDA receptors; AMPA receptors; neurotransmission; spike firing; developmental plasticity

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Received June 15, 2006; revised July 24, 2007; accepted July 26, 2007.

Correspondence should be addressed to Dr. Lu-Yang Wang, Division of Neurology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Email: luyang.wang{at}utoronto.ca

This article has been cited by other articles:

				J. S. Lee, M.-H. Kim, W.-K. Ho, and S.-H. Lee Presynaptic Release Probability and Readily Releasable Pool Size Are Regulated by Two Independent Mechanisms during Posttetanic Potentiation at the Calyx of Held Synapse J. Neurosci., August 6, 2008; 28(32): 7945 - 7953. [Abstract] [Full Text] [PDF]

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