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

Joshi, Indu; Yang, Yimei; Wang, Luyang

doi:10.1523/jneurosci.2506-07.2007

Cited by 25 publications

(32 citation statements)

References 43 publications

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“…During high-frequency bursting, MNTB neurons demonstrated a plateau depolarization in vivo. Plateau depolarizations have also been observed during high-frequency calyceal stimulation in slice recordings, and were shown to be NMDA-dependent (Futai et al 2001;Leão & von Gersdorff, 2002;Joshi et al 2007) and attenuated by presynaptic activation of adrenergic receptors (Leão & von Gersdorff, 2002). Our simulations in which we used the recorded VC activity as input to the HH-model were in agreement with an important role for NMDAR activity, even though for definitive confirmation pharmacological blockage would be needed.…”

Section: Plateau Potentialssupporting

confidence: 61%

“…; Leão & von Gersdorff, ; Joshi et al . ) and attenuated by presynaptic activation of adrenergic receptors (Leão & von Gersdorff, ). Our simulations in which we used the recorded VC activity as input to the HH‐model were in agreement with an important role for NMDAR activity, even though for definitive confirmation pharmacological blockage would be needed.…”

Section: Discussionmentioning

confidence: 99%

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In vivo matching of postsynaptic excitability with spontaneous synaptic inputs during formation of the rat calyx of Held synapse

Sierksma

Tedja

Borst

2016

The Journal of Physiology

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Key pointsr Neurons in the medial nucleus of the trapezoid body of anaesthetized rats of postnatal day (P)2-6 showed burst firing with a preferred interval of about 100 ms, which was stable, and a second preferred interval of 5-30 ms, which shortened during development.r In 3 out of 132 cases, evidence for the presence of two large inputs was found. r In vivo whole-cell recordings revealed that the excitability of the principal neuron and the size of its largest synaptic inputs were developmentally matched.r At P2-4, action potentials were triggered by barrages of small synaptic events that summated to plateau potentials, while at later stages firing depended on a single, large and often prespike-associated input, which is probably the nascent calyx of Held.r Simulations with a Hodgkin-Huxley-like model, which was based on fits of the intrinsic postsynaptic properties, suggested an essential role for the low-threshold potassium conductance in this transition. AbstractIn the adult, principal neurons of the medial nucleus of the trapezoid body (MNTB) are typically contacted by a single, giant terminal called the calyx of Held, whereas during early development a principal neuron receives inputs from many axons. How these changes in innervation impact the postsynaptic activity has not yet been studied in vivo. We therefore recorded spontaneous inputs and intrinsic properties of principal neurons in anaesthetized rat pups during the developmental period in which the calyx forms. A characteristic bursting pattern could already be observed at postnatal day (P)2, before formation of the calyx. At this age, action potentials (APs) were triggered by barrages of summating EPSPs causing plateau depolarizations. In contrast, at P5, a single EPSP reliably triggered APs, resulting in a close match between preand postsynaptic firing. Postsynaptic excitability and the size of the largest synaptic events were developmentally matched. The developmental changes in intrinsic properties were estimated by fitting in vivo current injections to a Hodgkin-Huxley-type model of the principal neuron. Our simulations indicated that the developmental increases in I h , low-threshold K + channels and leak currents contributed to the reduction in postsynaptic excitability, but that low-threshold K + channels specifically functioned as a dampening influence in the near-threshold range, thus precluding small inputs from triggering APs. Together, these coincident changes help to propagate bursting activity along the auditory brainstem, and are essential steps towards establishing the relay function of the calyx of Held synapse.

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Section: Plateau Potentialssupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

In vivo matching of postsynaptic excitability with spontaneous synaptic inputs during formation of the rat calyx of Held synapse

Sierksma

Tedja

Borst

2016

The Journal of Physiology

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“…Importantly, a number of models of delayed neurodegeneration imply that persistent downregulations of glutamate subunit types which permit increases in Ca 2+ permeability also occur in surviving cells of the retina, hippocampus, and spinal cord (Hof et al, 1998; Grossman et al, 1999; Vandenberghe et al, 2000). Additionally, prolonged application of NMDA can alter coupling of synaptic and perisynaptic/extrasynaptic NMDARs to group I mGluRs to influence the dynamics of NMDAR trafficking at the synapse (Joshi et al, 2007). In keeping with this, cultured retinal ganglion cells (RGCs) are resistant to direct application of NMDA and glutamate due to NMDA receptors being expressed extrasynaptically (Ullian et al, 2004), although RGCs are vulnerable after retinal ischemia and in glaucoma (Sucher et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Early exposure of cultured hippocampal neurons to excitatory amino acids protects from later excitotoxicity

Friedman

Segal

2009

Intl J of Devlp Neuroscience

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Status epilepticus occurring in early postnatal development protects CA1 hippocampal neurons, the region most sensitive to seizure-induced injury in the developing brain. Here, we developed a "two hit" model in dissociated cultures of the rat hippocampus to test whether pre-exposure of immature neurons to high concentrations of glutamate, N-methyl-D-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) during a relatively resistant period prevents neurons from dying following a second exposure to the same chemicals after neurons mature and become highly vulnerable to excitatory amino acids (EAAs). Cultures were exposed to varied doses of glutamate, NMDA, or AMPA for 48 h at 5 DIV and again at 14 DIV for 5, 15, or 30 min. NeuN immunohistochemistry showed early exposure to glutamate (500 microM) killed approximately half of the neurons (52+/-8.6%) compared to the marked depletion that occurs after one exposure at 14 DIV (98+/-0.79%). When cultures were first challenged with moderate doses of glutamate (200 microM) followed by the high dose 7 days later, a significant population of neurons was spared (35.3+/-1.2%). Similarly, pre-exposure to maximal doses of NMDA (100 microM) increased the proportion of surviving cells following the second challenge. In contrast, AMPA (100 microM) was equally toxic after early or late applications and did not protect from the second exposure. GluR1 subunit expression was markedly decreased at 48 h after one or two exposures to 200 microM glutamate (by 44.57+/-3.6%, 45.07+/-3.69%) whereas GluR2 subunit expression was reduced by a lesser amount (25.7 57+/-3.8%). Confocal microscopy showed that one or two exposures to NMDA caused GluR2 protein to downregulate even further whereas parvalbumin (PV) was dramatically increased in the same neurons by over four-fold. On the other hand, calbindin (CB) immunoreactivity was nearly absent after the first exposure to 500 microM glutamate. These data indicate that early, transient exposure to certain EAAs at high doses can induce long-lasting neuroprotection. Alterations in the GluR1/GluR2 ratio as well as differential expression of specific calcium binding proteins may contribute to this neuroprotection.

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“…We consider a possibility that PTP contributes to the maturation of calyx of Held synapse. Recently, Joshi et al (2007) reported that extrasynaptic NMDA receptors (NMDARs) are downregulated by pairing a depolarization of the postsynaptic neuron and burst stimulation of afferent axon fibers, probably by the mechanism of coincident activation of postsynaptic metabotropic glutamate receptors and NMDARs. It remains to be addressed whether such strong stimuli are possible under physiological conditions during a developmental period of hearing onset.…”

Section: Possible Physiological Role Of Ptp In Development Of Calyx Omentioning

confidence: 99%

Presynaptic Release Probability and Readily Releasable Pool Size Are Regulated by Two Independent Mechanisms during Posttetanic Potentiation at the Calyx of Held Synapse

Lee¹,

Kim²,

Ho³

et al. 2008

J. Neurosci.

118

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At the immature calyx of Held, the fast decay phase of a Ca 2ϩ transient induced by tetanic stimulation (TS) was followed by a period of elevated [Ca 2ϩ ] i for tens of seconds, referred to as posttetanic residual calcium (Ca res ). We investigated the source of Ca res and its contribution to posttetanic potentiation (PTP). After TS (100 Hz for 4 s), posttetanic Ca res at the calyx of Held was largely abolished by tetraphenylphosphonium (TPP ϩ ) or Ru360, which inhibit mitochondrial Na ϩ -dependent Ca 2ϩ efflux and Ca 2ϩ uniporter, respectively. Whereas the control PTP lasted longer than Ca res , inhibition of Ca res by TPP ϩ resulted in preferential suppression of the early phase of PTP, the decay time course of which well matched with that of Ca res . TS induced significant increases in release probability (P r ) and the size of the readily releasable pool (RRP), which were estimated from plots of cumulative EPSC amplitudes. TPP ϩ or Ru360 suppressed the posttetanic increase in P r , whereas it had little effect on the increase in RRP size. Moreover, the posttetanic increase in P r , but not in RRP size, showed a linear correlation with the amount of Ca res . In contrast, myosin light chain kinase (MLCK) inhibitors and blebbistatin reduced the posttetanic increase in RRP size with no effect on the increase in P r . Application of TPP ϩ in the presence of MLCK inhibitor peptide caused further suppression of PTP. These findings suggest that Ca res released from mitochondria and activation of MLCK are primarily responsible for the increase in P r and that in the RRP size, respectively.

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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

Cited by 25 publications

References 43 publications

In vivo matching of postsynaptic excitability with spontaneous synaptic inputs during formation of the rat calyx of Held synapse

In vivo matching of postsynaptic excitability with spontaneous synaptic inputs during formation of the rat calyx of Held synapse

Early exposure of cultured hippocampal neurons to excitatory amino acids protects from later excitotoxicity

Presynaptic Release Probability and Readily Releasable Pool Size Are Regulated by Two Independent Mechanisms during Posttetanic Potentiation at the Calyx of Held Synapse

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