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Lab Publications

Wong NF, Xu-Friedman MA (2022) Induction of activity-dependent plasticity at auditory nerve synapses. J Neurosci 42: 6211–6220. [pubmed]

  • This paper investigates the signalling pathway whereby sound-driven activity causes changes in auditory nerve synapses.

  • We elevated activity in vitro using high K+ and optogenetic stimulation, which drove a decrease in release probability.

  • Activation of postsynaptic NMDA and AMPA receptors appears to drive nitric oxide synthase to produce NO.

  • Treatment with an NO donor induces similar synaptic changes.

  • Previous noise exposure in vivo occludes further synaptic changes in vitro.

Burlingham SR, Wong NF, Peterkin L, Lubow L, Dos Santos Passos C, Benner O, Ghebrial M, Cast TP, Xu-Friedman MA, Südhof TC, Chanda S (2022) Induction of synapse formation by de novo neurotransmitter synthesis. Nat Commun 30: 3060. [pubmed]

  • This paper shows that overexpression of three key genes can convert excitatory neurons to inhibitory.

  • Our lab contributed evidence that this technique works in vivo, by turning auditory nerve fibers GABAergic.

Wong NF, Xu-Friedman MA (2022) Time course of activity-dependent changes in auditory nerve synapses reveals multiple underlying cellular mechanisms. J Neurosci 42: 2492–2502. [pubmed]

  • This paper shows that auditory nerve synapses change within 1 to 2 days of noise exposure or conductive hearing loss.

  • Structural changes take longer, about 7 days.

  • Recovery from noise exposure or conductive hearing loss is rapid.

  • Exposure to noise for 8 hr/day for one week leads to long-lasting synaptic changes.

Zhuang XW, Wong NF, Sun W, Xu-Friedman MA (2020) Mechanisms and functional consequences of presynaptic homeostatic plasticity at auditory nerve synapses. J Neurosci 40: 6896–6909. [pubmed]

  • This paper examines the mechanisms underlying changes in auditory nerve synapses in different acoustic conditions.

  • Experiments using chelators and imaging suggest acoustic conditions drive changes in calcium influx.  

  • Both juvenile and mature synapses are subject to activity-dependent changes.

  • Dynamic clamp experiments indicates that presynaptic changes have a major impact on spike fidelity.

Lauer AM, Dent ML, Sun W, Xu-Friedman MA (2019) Effects of non-traumatic noise and conductive hearing loss on auditory system function. Neurosci 407:182-191. [pubmed]

  • This review discusses the long-term consequences of abnormal acoustic activity on hearing.

Fischer AU, Müller NIC, Deller T, Del Turco D, Fisch JO, Griesemer D, Kattler K, Maraslioglu A, Roemer V, Xu-Friedman MA, Walter J, Friauf E (2019) GABA is a modulator, rather than a classical transmitter, in the medial nucleus of the trapezoid body-lateral superior olive sound localization circuit. J Physiol 597: 2269–2295. [pubmed]

  • This paper examines how GABA affects the synapses formed by MNTB neurons in the LSO.

  • GABA had been thought to play a role early in development.

  • This paper indicates glycine is the important neurotransmitter, and GABA serves as a neuromodulator.

  • Our involvement was to assist Alex Fischer with calcium imaging experiments in the paper.

Zhuang XW, Sun W, Xu-Friedman MA (2017) Changes in properties of auditory nerve synapses following conductive hearing loss. J Neurosci 37: 323–332. [pubmed]

  • This paper examines how long-term occlusion of the ear affects endbulbs.

  • After occlusion of the ear, endbulbs show increased depression.

  • Occlusion also leads to a decrease in vesicle pool size, and shrinking of the synapse.

  • Postsynaptically, bushy cells decrease input resistance, leading to decreased spiking.

  • These changes appear to enhance efficiency under low-activity conditions.

Yang Y, Ramamurthy B, Neef A, Xu-Friedman MA (2016) Low somatic sodium conductance enhances action potential precision in time-coding auditory neurons. J Neurosci 36: 11999–12009. [pubmed]

  • This paper examines why bushy cells have low spike amplitudes

  • Bushy cells have Na channels with low density, and relatively hyperpolarized inactivation sensitivity.

  • Adding Na channels to bushy cells with dynamic clamp increases spike amplitudes.

  • However, increased spike amplitude recruits K channels, which reduces evoked spiking.

  • Na channels amplify EPSPs, which reduces the precision of coincidence detection.

  • This may explain why small spikes are adaptive in time-coding neurons like bushy cells.

Ngodup T, Goetz JA, McGuire BC, Sun W, Lauer AM, Xu-Friedman MA (2015) Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers. Proc Natl Acad Sci U S A. 112: 6479-6484. [pubmed]

NSF’s Science 360, WAMC’s Academic Minute

  • This paper examines how long-term exposure to loud, but non-damaging noise affects endbulbs.

  • After noise-rearing, endbulbs show less depression, and even facilitation.

  • Noise-rearing also leads to an increase in vesicle pool size.

  • Postsynaptically, bushy cells decrease spike threshold, but there is no evident change in postsynaptic receptors.

  • These pre- and postsynaptic changes lead to enhanced spiking during intense levels of activity.

Yang Y, Xu-Friedman MA. (2015) Different pools of glutamate receptors mediate sensitivity to ambient glutamate in the cochlear nucleus. J Neurophysiol 113: 3634-45. [pubmed]

  • Tonic levels of glutamate activate NMDA receptors as well as mGluRs.

  • The receptors are primarily extrasynaptic, but also some synaptic.

  • Slight changes in tonic glutamate cause significant shifts in membrane potential and spiking probability.

Yang H, Xu-Friedman MA. (2015) Skipped-stimulus approach reveals that short-term plasticity dominates synaptic strength during ongoing activity. J Neurosci 35: 8297-307. [pubmed]

  • This paper examines short-term plasticity during on-going activity.

  • We develop a new approach using trains of stimuli with one skipped to show that one EPSC influences subsequent release.

  • This amount of depression has a significant effect on spike probability.

Yang Y, Adowski, T, Ramamurthy B, Neef A, Xu-Friedman MA (2015) High-speed dynamic-clamp interface. J Neurophysiol 113: 2713–20. [pubmed]

  • This paper describes the operation and capabilities of a dynamic clamp interface.

  • The dynamic clamp runs very rapidly, and can implement leak, synaptic, and channel conductances.

  • The dynamic clamp also includes a test mode to allow testing of its speed and reliability.

Yang H, Xu-Friedman MA (2013) Stochastic properties of neurotransmitter release expand the dynamic range of synapses. J Neurosci 33: 14406–16. [pubmed]

  • This paper investigates how the inherent randomness of neurotransmitter release affects the transfer of information

  • Because EPSPs vary so much from trial to trial, even an EPSP that is below threshold on average can still trigger action potentials occasionally.

  • Sound features that cause synaptic depression can still be represented in bushy cell spiking.

  • However, random variability in amplitude also leads to variability in the timing of spikes.

Xu-Friedman MA (2013) Illustrating concepts of quantal analysis with an intuitive classroom model. Adv Physiol Educ 37: 112–6. [pubmed]

  • This paper describes a classroom activity to help explain quantal analysis to students of neurobiology using two analogies.

  • One analogy uses the weights of packages to figure out the number of M&M’s inside.

  • The second analogy quantifies the distribution of M&M colours as an example of a Poisson distribution.

Yang H, Xu-Friedman MA. (2012) Emergence of coordinated plasticity in the cochlear nucleus and cerebellum. J Neurosci 32: 7862-8. [pubmed]

  • This paper examines the properties of endbulbs that converge on the same bushy cell.

  • Converging endbulbs have characteristics of depression that are more similar than endbulbs that target different bushy cells.

  • Converging endbulbs have similar probability of neurotransmitter release.

  • This similarity emerges after the onset of hearing.

Chanda S, Xu-Friedman MA. (2011) Excitatory modulation in the cochlear nucleus through group I metabotropic glutamate receptor activation. J Neurosci 31: 7450-5. [pubmed]

  • Group I mGluRs depolarize bushy cells

  • Tonic levels of glutamate activate mGluRs, contributing to resting potential

  • Activation of mGluRs enhances spiking, and can offset the effects of GABA receptor activation

Chanda S, Oh S, and Xu-Friedman MA (2011) Calcium imaging of auditory nerve fiber terminals in the cochlear nucleus. J Neurosci Methods 195: 24–29. [pubmed]

  • This paper develops a technique for measuring presynaptic calcium levels at auditory nerve synapses

Yang H, Xu-Friedman MA. (2010) Developmental mechanisms for suppressing the effects of delayed release at the endbulb of Held. J Neurosci 30: 11466-75. [pubmed]

  • This paper investigates the role of delayed release, which is a low level of release of individual vesicles, that lasts for 100’s of ms after the normal, synchronous EPSC.

  • Delayed release is prominent in synapses of all ages, and can trigger spikes in immature synapses.

  • Delayed release drives spikes less effectively after the onset of hearing, probably because of upregulation of K channels.

  • Delayed release competes for the same pool of vesicles as regular EPSCs.

Chanda S, Xu-Friedman MA. (2010) Neuromodulation by GABA converts a relay into a coincidence detector. J Neurophysiol 104: 11466-75. [pubmed]

  • This paper investigates the effects of GABA receptor activation

  • Ionotropic GABA receptors inhibit the cell, but are mainly extrasynaptic

  • Metabotropic GABA receptors reduce the amoung of presynaptic neurotransmitter release

  • Activation of either renders single synaptic inputs ineffective, so multiple inputs must be activated nearly simultaneously.

Chanda S, Xu-Friedman M A. (2010) A low-affinity antagonist reveals saturation and desensitization in mature synapses in the auditory brainstem. J Neurophysiol 103: 1915-26. [pubmed]

  • This paper refines approaches for studying desensitization and saturation using low-affinity receptor antagonists.

  • The results confirm that desensitization and saturation affect AMPA-receptor-mediated EPSCs in immature as well as older endbulbs.

Pliss L, Yang H, Xu-Friedman MA. (2009) Context-dependent effects of NMDA receptors on precise timing information at the endbulb of Held in the cochlear nucleus. J Neurophysiol 102: 2627-37. [pubmed]

  • This paper addresses the role of NMDA receptors at endbulbs.

  • Both AMPA- and NMDA-receptor mediated EPSCs depress considerably, but NMDA EPSCs summate temporally.

  • NMDA-receptor-mediated EPSCs compensate in part for AMPA EPSC depression and increase spike probability.

Yang H, Xu-Friedman MA. (2009) Impact of synaptic depression on spike timing at the endbulb of Held. J Neurophysiol 102: 1699-710. [pubmed]

  • This paper investigates the consequences of depression on spiking using dynamic clamp.

  • Endbulbs with stronger depression and higher rates of activity reduced spiking in bushy cells.

Yang H, Xu-Friedman MA. (2008) Relative roles of different mechanisms of depression at the mouse endbulb of Held. J Neurophysiol 99: 2510-21. [pubmed]

  • This paper examines the mechanisms underlying depression at endbulbs.

  • AMPA-receptor-mediated EPSCs depress as a result of desensitization and a presynaptic process that is most likely vesicle depletion.

  • NMDA-receptor-mediated EPSCs depress as a result of receptor saturation.


Collaborations & Reviews

Toal KL, Radziwon KE, Holfoth DP, Xu-Friedman MA, and Dent ML (2016) Audiograms, gap detection thresholds, and frequency difference limens in cannabinoid receptor 1 knockout mice. Hear Res 332: 217–222. [pubmed]

Klug A, Borst JGG, Carlson BA, Kopp-Scheinpflug C, Klyachko VA, and Xu-Friedman MA (2012) How do short-term changes at synapses fine-tune information processing? J Neurosci 32: 14058-14063. [pubmed]

  • This review summarizes a symposium from the 2012 Society for Neuroscience Meeting

Wei L, Ding D, Sun W, Xu-Friedman MA, and Salvi RJ (2010) Effects of sodium salicylate on spontaneous and evoked spike rate in the dorsal cochlear nucleus. Hear Res 267: 54–60. [pubmed]

Radziwon KE, June KM, Stolzberg DJ, Xu-Friedman MA, Salvi RJ, and Dent ML (2009) Behaviorally measured audiograms and gap detection thresholds in CBA/CaJ mice. J Comp Physiol A 195: 961-969. [pubmed]

Strenzke N, Chanda S, Kopp-Scheinpflug C, Khimich D, Reim K, Bulankina AV, Neef A, Wolf F, Brose N, Xu-Friedman MA, Moser T. (2009) Complexin-I is required for high-fidelity transmission at the endbulb of Held auditory synapse. J Neurosci 29: 7991-8004. [pubmed]

  • This paper investigates the role of complexin-1 in neurotransmitter release.

  • Mutants have disrupted hearing, but normal cochlear function.

  • Mutant endbulbs have greatly reduced neurotransmitter release, which probably accounts for increased thresholds.

Xu-Friedman MA (2009) Synaptic Depression. In: Encyclopedia of Neuroscience, volume 9 (Squire LR, Ed.), pp. 725-730. Oxford: Academic Press.

Xu-Friedman MA and Regehr WG (2004) Structural contributions to short-term synaptic plasticity. Physiol Rev 84: 69–85. [pubmed]

Xu-Friedman MA and Hopkins CD (1999) Central mechanisms of temporal analysis in the knollenorgan pathway of mormyrid electric fish.  J Exp Biol 202: 1311–1318. [pubmed]

Carr CE and Friedman MA (1999) Evolution of time coding systems.  Neural Comput 11: 1–20. [pubmed]


Earlier work

Xu-Friedman MA and Regehr WG (2005) Dynamic-clamp analysis of the effects of convergence on spike timing I: Many synaptic inputs. J Neurophysiol 94: 2512–2525. [pubmed]

  • This paper investigates how multiple converging synaptic inputs influence the probability and timing of postsynaptic spiking

Xu-Friedman MA and Regehr WG (2005) Dynamic-clamp analysis of the effects of convergence on spike timing II: Few synaptic inputs. J Neurophysiol 94: 2526–2534. [pubmed]

  • This paper examines how a few, large converging synaptic inputs influence spike timing

Xu-Friedman MA and Regehr WG (2003) Ultrastructural contributions to desensitization at cerebellar mossy fiber to granule cell synapses. J Neurosci 23: 2182–2192. [pubmed]

  • This paper investigates the basis for desensitization at synapses

    • Release sites of mossy fibers are packed closely together, enhancing the likelihood of desensitization of postsynaptic receptors

Xu-Friedman MA, Harris KM, and Regehr WG (2001) Three-dimensional comparison of ultrastructural characteristics at depressing and facilitating synapses onto cerebellar Purkinje cells. J Neurosci 21: 6666–6672. [pubmed]

  • This paper investigates the basis for differences in the probability of release at synapses

  • Climbing fiber and parallel fiber synapses have extremely different release probability

  • However, they have very similar number of docked vesicles, suggesting this cannot explain the physiological differences

Xu-Friedman MA and Regehr WG (2000) Probing fundamental aspects of synaptic transmission with strontium. J Neurosci 20: 4414–4422. [pubmed]

  • This paper addresses the many ways synaptic transmission is altered by strontium

  • The cooperativity is slightly different, delayed release is enhanced, facilitation is greater and of longer duration

  • These effects can be explained by the prolonged presence of strontium in the presynaptic terminal, yet driving calcium-dependent processes less effectively

Xu-Friedman MA and Regehr WG (1999) Presynaptic strontium dynamics and synaptic transmission.  Biophys J 76: 2029–2042. [pubmed]

  • This paper sets out how to study strontium dynamics using calcium-sensitive fluorescence dyes

Friedman MA and Hopkins CD (1998) Neural substrates for species recognition in the time-coding electrosensory pathway of mormyrid electric fish.  J Neurosci 18: 1171–1185. [pubmed]

  • This paper examines the central mechanisms for measuring electric pulse duration

Amagai S, Friedman MA and Hopkins CD (1998) Time-coding in the midbrain of mormyrid electric fish I: Physiology and anatomy of cells in the nucleus exterolateralis pars anterior (ELa). J Comp Physiol A 182: 115-130. [pubmed]

Friedman MA and Kawasaki M (1997) Calretinin immunoreactivity in mormyrid and gymnarchid electrosensory and electromotor systems. J Comp Neurol 387: 341–357. [pubmed]

  • This paper describes the relationship between the calcium-binding protein calretinin and important brain structures in the electrosensory system

Friedman MA and Hopkins CD (1996) Tracking mormyrid electric fish in the field using individual differences in electric organ discharges. Anim Behav 51: 391–407.

  • This paper develops a technique for studying electric fish behavior, using the discharge to identify individual fish

Smith WC, Friedman MA, and Goldsmith TH (1992) Retinoids in the lateral eye of Limulus: Evidence for a retinal photoisomerase. Vis Neurosci 8: 329–336. [pubmed]

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