Different pools of glutamate receptors mediate sensitivity to ambient glutamate in the cochlear nucleus

Yang, Yang; Xu‐Friedman, Matthew A.

doi:10.1152/jn.00693.2014

Cited by 7 publications

(6 citation statements)

References 63 publications

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“…To test this, we used the irreversible, activity-dependent NMDAR antagonist MK-801 to assess the level of ambient synaptic glutamate-induced activation of synaptic NMDARs, and whether this level differs between excitatory and inhibitory neurons. We first recorded NMDAR EPSCs (−60 mV, 0.5 mM Mg 2+ ) to establish a baseline response, and paused stimulation while voltage-clamping the postsynaptic neurons at +40 mV in the presence of MK-801 (20 μM) to block synaptic NMDARs activated by ambient glutamate 25 , 59 . After 5 min, the holding potential was switched back to −60 mV with synaptic stimulation resumed.…”

Section: Resultsmentioning

confidence: 99%

Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity

Yao

Grand

Hanson³

et al. 2018

Nat Commun

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Selective disruption of synaptic drive to inhibitory neurons could contribute to the pathophysiology of various brain disorders. We have previously identified a GluN2A-selective positive allosteric modulator, GNE-8324, that selectively enhances N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic responses in inhibitory but not excitatory neurons. Here, we demonstrate that differences in NMDAR subunit composition do not underlie this selective potentiation. Rather, a higher ambient glutamate level in the synaptic cleft of excitatory synapses on inhibitory neurons is a key factor. We show that increasing expression of glutamate transporter 1 (GLT-1) eliminates GNE-8324 potentiation in inhibitory neurons, while decreasing GLT-1 activity enables potentiation in excitatory neurons. Our results reveal an unsuspected difference between excitatory synapses onto different neuronal types, and a more prominent activation of synaptic NMDARs by ambient glutamate in inhibitory than excitatory neurons. This difference has implications for tonic NMDAR activity/signaling and the selective modulation of inhibitory neuron activity to treat brain disorders.

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Section: Resultsmentioning

confidence: 99%

Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity

Yao

Grand

Hanson³

et al. 2018

Nat Commun

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“…The idea of RMP modulation by endogenous ACh has also been proposed for fusiform and cartwheel cells of the DCN ( Godfrey et al, 1998 ). It has also been shown that the SBC RMP is set by endogenous glutamate through mGluRs ( Chanda and Xu-Friedman, 2011 ; Yang and Xu-Friedman, 2015 ). Although we could represent the muscarinic effect only in a simplified form in the model, some general conclusions can be drawn from our in silico experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, SBCs are often seen as a simple relay. However, a number of studies have shown that SBC activity is not only affected by the excitatory ANF input: the resting membrane potential and action potential probability of SBCs are under the influence of slow inhibitory synaptic inputs ( Kuenzel et al, 2011, 2015 ; Nerlich et al, 2014a ; Keine and Rübsamen, 2015 ) and metabotropic glutamate receptors ( Chanda and Xu-Friedman, 2011 ; Yang and Xu-Friedman, 2015 ). Additionally, SBC activity is influenced by GABA B receptors ( Chanda and Xu-Friedman, 2010 ) and the dynamics of voltage-activated conductance ( Cao et al, 2007 ; Oertel et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Slow Cholinergic Modulation of Spike Probability in Ultra-Fast Time-Coding Sensory Neurons

Goyer

Kurth

Gillet

et al. 2016

eNeuro

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Sensory processing in the lower auditory pathway is generally considered to be rigid and thus less subject to modulation than central processing. However, in addition to the powerful bottom-up excitation by auditory nerve fibers, the ventral cochlear nucleus also receives efferent cholinergic innervation from both auditory and nonauditory top–down sources. We thus tested the influence of cholinergic modulation on highly precise time-coding neurons in the cochlear nucleus of the Mongolian gerbil. By combining electrophysiological recordings with pharmacological application in vitro and in vivo, we found 55–72% of spherical bushy cells (SBCs) to be depolarized by carbachol on two time scales, ranging from hundreds of milliseconds to minutes. These effects were mediated by nicotinic and muscarinic acetylcholine receptors, respectively. Pharmacological block of muscarinic receptors hyperpolarized the resting membrane potential, suggesting a novel mechanism of setting the resting membrane potential for SBC. The cholinergic depolarization led to an increase of spike probability in SBCs without compromising the temporal precision of the SBC output in vitro. In vivo, iontophoretic application of carbachol resulted in an increase in spontaneous SBC activity. The inclusion of cholinergic modulation in an SBC model predicted an expansion of the dynamic range of sound responses and increased temporal acuity. Our results thus suggest of a top–down modulatory system mediated by acetylcholine which influences temporally precise information processing in the lower auditory pathway.

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“…Furthermore, the strong voltagedependent magnesium block of most NMDARs limits their ability to pass a physiologically relevant tonic current (Vicini et al, 1998). Despite this, tonic activation of NMDARs has been shown to influence excitability in a variety of neuronal subtypes across multiple brain regions (Sah et al, 1989;Chergui et al, 1993;Moos et al, 1997;Dalby and Mody, 2003;Le Meur et al, 2007;Povysheva and Johnson, 2012), including at times when the target neurons are not artificially depolarized (Yang and Xu-Friedman, 2015;Riebe et al, 2016). Based on their unique properties, including high glutamate affinity and low-magnesium affinity, GluN2C/DRs have been hypothesized to be the primary mediators of a glutamatergic tonic current (Le Meur et al, 2007;Riebe et al, 2016).…”

Section: In Sensitivity To Ambient Glutamatementioning

confidence: 99%

Tonic Activation of GluN2C/GluN2D-Containing NMDA Receptors by Ambient Glutamate Facilitates Cortical Interneuron Maturation

et al. 2019

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Developing cortical GABAergic interneurons rely on genetic programs, neuronal activity, and environmental cues to construct inhibitory circuits during early postnatal development. Disruption of these events can cause long-term changes in cortical inhibition and may be involved in neurological disorders associated with inhibitory circuit dysfunction. We hypothesized that tonic glutamate signaling in the neonatal cortex contributes to, and is necessary for, the maturation of cortical interneurons. To test this hypothesis, we used mice of both sexes to quantify extracellular glutamate concentrations in the cortex during development, measure ambient glutamate-mediated activation of developing cortical interneurons, and manipulate tonic glutamate signaling using subtype-specific NMDA receptor antagonists in vitro and in vivo. We report that ambient glutamate levels are high (Ϸ100 nM) in the neonatal cortex and decrease (to Ϸ50 nM) during the first weeks of life, coincident with increases in astrocytic glutamate uptake. Consistent with elevated ambient glutamate, putative parvalbumin-positive interneurons in the cortex (identified using G42:GAD1-eGFP reporter mice) exhibit a transient, tonic NMDA current at the end of the first postnatal week. GluN2C/GluN2D-containing NMDA receptors mediate the majority of this current and contribute to the resting membrane potential and intrinsic properties of developing putative parvalbumin interneurons. Pharmacological blockade of GluN2C/GluN2D-containing NMDA receptors in vivo during the period of tonic interneuron activation, but not later, leads to lasting decreases in interneuron morphological complexity and causes deficits in cortical inhibition later in life. These results demonstrate that dynamic ambient glutamate signaling contributes to cortical interneuron maturation via tonic activation of GluN2C/ GluN2D-containing NMDA receptors. Inhibitory GABAergic interneurons make up 20% of cortical neurons and are critical to controlling cortical network activity. Dysfunction of cortical inhibition is associated with multiple neurological disorders, including epilepsy. Establishing inhibitory cortical networks requires in utero proliferation, differentiation, and migration of immature GABAergic interneurons, and subsequent postnatal morphological maturation and circuit integration. Here, we demonstrate that ambient glutamate provides tonic activation of immature, putative parvalbumin-positive GABAergic interneurons in the neonatal cortex via high-affinity NMDA receptors. When this activation is blocked, GABAergic interneuron maturation is disrupted, and cortical networks exhibit lasting abnormal hyperexcitability. We conclude that temporally precise activation of developing cortical interneurons by ambient glutamate is critically important for establishing normal cortical inhibition.

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Different pools of glutamate receptors mediate sensitivity to ambient glutamate in the cochlear nucleus

Cited by 7 publications

References 63 publications

Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity

Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity

Slow Cholinergic Modulation of Spike Probability in Ultra-Fast Time-Coding Sensory Neurons

Tonic Activation of GluN2C/GluN2D-Containing NMDA Receptors by Ambient Glutamate Facilitates Cortical Interneuron Maturation

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