Context-Dependent Effects of NMDA Receptors on Precise Timing Information at the Endbulb of Held in the Cochlear Nucleus

Pliss, Lioudmila; Yang, Hua; Xu‐Friedman, Matthew A.

doi:10.1152/jn.00111.2009

Cited by 33 publications

(30 citation statements)

References 57 publications

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“…The GBC-to-MNTB pathway has already been known to incorporate a number of striking structural and functional adaptations for fast and reliable processing: the end bulb of Held (30,31), superior phase locking in GBCs compared with their inputs (32), the calyx of Held giant synapse (18) and, discovered most recently, an unusual myelination pattern in GBCs tuned to lower frequencies associated with superior conductance velocity and temporal precision (28). We determined that in mice no such specializations in conduction velocity and precision were present, and mouse GBC axons conformed with standard internode length to axon caliber ratios irrespective of frequency tuning.…”

Section: Discussionmentioning

confidence: 99%

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem

Stange-Marten¹,

Nabel²,

Sinclair³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Precise timing of synaptic inputs is a fundamental principle of neural circuit processing. The temporal precision of postsynaptic input integration is known to vary with the computational requirements of a circuit, yet how the timing of action potentials is tuned presynaptically to match these processing demands is not well understood. In particular, action potential timing is shaped by the axonal conduction velocity and the duration of synaptic transmission delays within a pathway. However, it is not known to what extent these factors are adapted to the functional constraints of the respective circuit. Here, we report the finding of activity-invariant synaptic transmission delays as a functional adaptation for input timing adjustment in a brainstem sound localization circuit. We compared axonal and synaptic properties of the same pathway between two species with dissimilar timing requirements (gerbil and mouse): In gerbils (like humans), neuronal processing of sound source location requires exceptionally high input precision in the range of microseconds, but not in mice. Activityinvariant synaptic transmission and conduction delays were present exclusively in fast conducting axons of gerbils that also exhibited unusual structural adaptations in axon myelination for increased conduction velocity. In contrast, synaptic transmission delays in mice varied depending on activity levels, and axonal myelination and conduction velocity exhibited no adaptations. Thus, the specializations in gerbils and their absence in mice suggest an optimization of axonal and synaptic properties to the specific demands of sound localization. These findings significantly advance our understanding of structural and functional adaptations for circuit processing. myelination | synaptic transmission delay | sound localization | circuit processing | input timing T emporal integration of bioelectrical signals via chemical synapses is fundamental to neuronal computations. During circuit processing, neuronal information transfer via action potentials is controlled by exact differences in the occurrence between excitatory and inhibitory inputs (1-5). The arrival time of inputs within circuits in turn is largely shaped by the conduction delay of action potentials along the axons and during synaptic transmission. During ongoing activity, the transmission delays of chemical synapses generally increase in the range of hundreds of microseconds due to short-term adaptations (6-9). However, because temporal integration on postsynaptic neurons usually operates on time scales in the range of milliseconds or even longer (10, 11), sluggishness arising from synaptic mechanisms and axonal conductance is negligible for most of these computations. There are, however, some essential neuronal processing tasks that challenge the temporal precision of our nervous system. For instance, weakly electric fish detect miniature changes in the frequency of a constant electrical field. The neuronal circuits in these animals use electrical instead of chemical synapses in t...

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Section: Discussionmentioning

confidence: 99%

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem

Stange-Marten¹,

Nabel²,

Sinclair³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus desensitization could curtail the responses of mature BCs during brief, intense sounds, which could influence auditory perception. This would also be influenced by additional factors, including NMDA receptor activation (Pliss et al 2009), delayed release, and spontaneous firing in AN fibers (Hermann et al 2007;Taberner and Liberman 2005).…”

Section: Functional Relevancementioning

confidence: 99%

A Low-Affinity Antagonist Reveals Saturation and Desensitization in Mature Synapses in the Auditory Brain Stem

Chanda

Xu‐Friedman

2010

Journal of Neurophysiology

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Chanda S, Xu-Friedman MA. A low-affinity antagonist reveals saturation and desensitization in mature synapses in the auditory brain stem. J Neurophysiol 103: 1915-1926, 2010. First published January 27, 2010 doi:10.1152/jn.00751.2009. Postsynaptic receptor desensitization has been observed to contribute to depression in immature synapses. However, it is not clear whether desensitization persists and causes depression in mature synapses. We investigate this issue at the endbulb of Held, the synapse made by auditory nerve (AN) fibers onto bushy cells (BCs) of the anteroventral cochlear nucleus, where depression could influence the processing of sound information. Experiments using cyclothiazide (CTZ) have implicated desensitization in endbulbs from postnatal day 16 (P16) to P21 mice, but application of ␥-D-glutamylglycine (DGG) did not reveal desensitization in endbulbs ϾP22. To reconcile these findings, we have studied the effects of both CTZ and DGG on endbulbs from P5 to P40 CBA/CaJ mice. In paired-pulse protocols, both CTZ and DGG reduced depression in all ages at intervals Ͻ10 ms, consistent with their effects preventing desensitization. However, DGG increased depression at intervals Ͼ20 ms, consistent with DGG's use to prevent saturation. DGG application revealed receptor saturation even under conditions of very low release probability. Preventing desensitization by CTZ occluded the effects of DGG on desensitization and revealed the effects of saturation at short intervals. We developed an approach to separate DGG's effect on saturation from its effect on desensitization, which showed that desensitization has an impact during bursts of auditory nerve activity. Dynamic-clamp experiments indicated that desensitization can reduce BC spike probability and increase latency and jitter. Thus desensitization may affect sound processing in the mature auditory system.

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“…It is striking that BCs utilize NMDARs, because the slow kinetics of NMDARs could be seen as incompatible with the role of BCs in relaying highly precise timing information about sounds. NMDARs are downregulated over development (Bellingham et al 1998), but they are not completely eliminated, and provide significant excitation on the fast timescale of synaptic transmission, particularly when the AMPA component is depressed (Pliss et al 2009). The present experiments indicate an additional role for NMDARs in supporting BC excitability over longer time scales regulated by ambient glutamate.…”

Section: Discussionmentioning

confidence: 99%

“…This coincides with a dramatic acceleration in NMDAR EPSC kinetics. By contrast, ifenprodil sensitivity persists in the endbulb, and NMDAR EPSCs show little acceleration after the onset of hearing (Pliss et al 2009). This presumably reflects differences in the functional role of NMDARs between the two synapses, despite their superficial similarity.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental procedures were approved by Institutional Animal Care and Use Committee. Slices were prepared from postnatal day (P) 14 to P21 and P35 to P40 CBA/CaJ mouse AVCN, as described previously (Chanda and Xu-Friedman 2010a;Pliss et al 2009;Xu-Friedman 2008, 2009). Briefly, sagittal slices were cut in an ice-cold solution containing the following (in mM): 76 NaCl, 75 sucrose, 25 NaHCO 3 , 25 glucose, 2.5 KCl, 1.25 NaH 2 PO 4 , 7 MgCl 2 , 0.5 CaCl 2 .…”

Section: Methodsmentioning

confidence: 99%

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

Yang

Xu‐Friedman

2015

Journal of Neurophysiology

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Yang Y, Xu-Friedman MA. Different pools of glutamate receptors mediate sensitivity to ambient glutamate in the cochlear nucleus. J Neurophysiol 113: 3634 -3645, 2015. First published April 8, 2015 doi:10.1152/jn.00693.2014.-Ambient glutamate plays an important role in pathological conditions, such as stroke, but its role during normal activity is not clear. In addition, it is not clear how ambient glutamate acts on glutamate receptors with varying affinities or subcellular localizations. To address this, we studied "endbulb of Held" synapses, which are formed by auditory nerve fibers onto bushy cells (BCs) in the anteroventral cochlear nucleus. When ambient glutamate was increased by applying the glutamate reuptake inhibitor TFB-TBOA, BCs depolarized as a result of activation of N-methyl-D-aspartate receptors (NMDARs) and group I metabotropic glutamate receptors (mGluRs). Application of antagonists against NMDARs (in 0 Mg 2ϩ ) or mGluRs caused hyperpolarization, indicating that these receptors were bound by a tonic source of glutamate. AMPA receptors did not show these effects, consistent with their lower glutamate affinity. We also evaluated the subcellular localization of the receptors activated by ambient glutamate. The mGluRs were not activated by synaptic stimulation and thus appear to be exclusively extrasynaptic. By contrast, NMDARs in both synaptic and extrasynaptic compartments were activated by ambient glutamate, as shown using the use-dependent antagonist MK-801. Levels of ambient glutamate appeared to be regulated in a spike-independent manner, and glia likely play a major role. These low levels of ambient glutamate likely have functional consequences, as even low concentrations of TBOA caused significant increases in BC spiking following synaptic stimulation. These results indicate that normal resting potential appears to be poised in the region of maximal sensitivity to small changes in ambient glutamate.

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Context-Dependent Effects of NMDA Receptors on Precise Timing Information at the Endbulb of Held in the Cochlear Nucleus

Cited by 33 publications

References 57 publications

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem

A Low-Affinity Antagonist Reveals Saturation and Desensitization in Mature Synapses in the Auditory Brain Stem

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

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