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

Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY 14260, USA.
Journal of Neurophysiology (Impact Factor: 2.89). 04/2010; 103(4):1915-26. DOI: 10.1152/jn.00751.2009
Source: PubMed


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 γ-D-glutamylglycine (DGG) did not reveal desensitization in endbulbs >P22. 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 <10 ms, consistent with their effects preventing desensitization. However, DGG increased depression at intervals >20 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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    • "Xu-Friedman and colleagues have investigated this issue in depth at synapses made by auditory nerve fibers onto bushy cells in the anteroventral cochlear nucleus of the mouse. These synapses, called " endbulbs of Held " , consistently show depression, while auditory nerve synapses onto neighboring Tstellate cells show less depression, or even facilitation (Isaacson and Walmsley, 1996; Cao and Oertel, 2010; Chanda and Xu-Friedman, 2010). Endbulbs vary in the amount of depression they show, and dynamic clamp experiments indicate that this has consequences for bushy cell spiking (Yang and Xu-Friedman, 2009). "
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    ABSTRACT: Synaptic transmission is highly dependent on recent activity and can lead to depression or facilitation of synaptic strength. This phenomenon is called "short-term synaptic plasticity" and is shown at all synapses. While much work has been done to understand the mechanisms of short-term changes in the state of synapses, short-term plasticity is often thought of as a mechanistic consequence of the design of a synapse. This review will attempt to go beyond this view and discuss how, on one hand, complex neuronal activity affects the short-term state of synapses, but also how these dynamic changes in synaptic strength affect information processing in return.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 10/2012; 32(41):14058-14063. DOI:10.1523/JNEUROSCI.3348-12.2012 · 6.34 Impact Factor
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    • "solid symbols of panel Ai). The distance measure incorporates PPR as well as EPSC amplitudes from the initial 7 pulses during 100, 200, and 333 Hz trains when desensitization is significant (Chanda and Xu-Friedman, 2010) (i.e. ). The difference in distributions is not significant (K-S test: P = 0.16, N C = 11, N NC = 24). "
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    ABSTRACT: Synapses formed by one cell type onto another cell type tend to show characteristic short-term plasticity, which varies from facilitating to depressing depending on the particular system. Within a population of synapses, plasticity can also be variable, and it is unknown how this plasticity is determined on a cell-by-cell level. We have investigated this in the mouse cochlear nucleus, where auditory nerve (AN) fibers contact bushy cells (BCs) at synapses called "endbulbs of Held." Synapses formed by different AN fibers onto one BC had plasticity that was more similar than would be expected at random. Experiments using MK-801 indicated that this resulted in part from similarity in the presynaptic probability of release. The similarity was not present in immature synapses but emerged after the onset of hearing. In addition, the phenomenon occurred at excitatory synapses in the cerebellum. This indicates that postsynaptic cells coordinate the plasticity of their inputs, which suggests that plasticity is of fundamental importance to synaptic function.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2012; 32(23):7862-8. DOI:10.1523/JNEUROSCI.0167-12.2012 · 6.34 Impact Factor
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    • "). In voltageclamp , BCs were identified by paired-pulse depression and fast EPSC kinetics (Chanda and Xu-Friedman, 2010b). Methods for perforated-patch recordings are described in Chanda and Xu-Friedman (2010a). "
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    ABSTRACT: Activation of group I metabotropic glutamate receptors (mGluRs) has been suggested to modulate development of auditory neurons. However, the acute effects of mGluR activation on physiological response properties are unclear. To address this, we studied the effects of mGluRs in bushy cells (BCs) of the mammalian anteroventral cochlear nucleus (AVCN). Activation of mGluRs with dihydroxyphenylglycine (DHPG) caused depolarization of BCs in mice as old as P42, but did not affect neurotransmitter release by presynaptic auditory nerve (AN) fibers. Application of mGluR antagonists indicated that mGluRs are tonically active, and are highly sensitive to small elevations in ambient glutamate by the glutamate reuptake blocker threo-β-benzyloxyaspartic acid (TBOA). mGluR-mediated depolarization enhanced the firing probability in response to AN stimulation, and reduced the latency and jitter. Furthermore, excitation through postsynaptic mGluRs can significantly counterbalance the inhibitory effects of presynaptic GABA(B) receptors. Thus, interaction between these two modulatory pathways may provide additional flexibility for fine-tuning the BC relay.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2011; 31(20):7450-5. DOI:10.1523/JNEUROSCI.1193-11.2011 · 6.34 Impact Factor
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