Lu-Yang Wang, PhD
Interim Head and Senior Scientist
Neurosciences & Mental Health
University of Toronto
Professor & Director
The BRAIN Platform, Department of Physiology
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- Excitatory synaptic transmission
- Voltage-gated calcium and potassium channels
- Neurotransmitter release and replenishment
- Glutamate receptors
- Neurotrophic ractors
- Auditory brainstem
Communication between neurons in the central nervous system is achieved primarily through highly specialized anatomical structures, known as chemical synapses. The efficacy of synaptic transmission largely lies within the ability of presynaptic terminals to release small vesicles containing neurotransmitters and the ability of postsynaptic receptors to respond to the released substances.
Using a giant synapse, namely the calyx of Held, in the mouse/rat auditory brainstem as a model system, we employ a number of biophysical approaches (i.e. patch-clamping, optical fluorescent imaging and photolysis in living brainstem slices) as well as pharmacological, immunochemical and molecular biological techniques to study critical elements for synaptic strength, fidelity and gain control in response to high-frequency stimuli.
Our study may provide important insights into the cellular and molecular mechanisms responsible for various forms of neuronal plasticity as well for acoustic sensory information processing, hearing loss, deafness and audiogenic seizures.
Our laboratory has two main research areas:
- Mechanisms underlying presynaptic neurotransmitter release and replenishment.
It is generally accepted that there are multiple pools of synaptic vesicles in the presynaptic terminal (i.e. the readily-releasable pool; the reserved pool). By making direct recordings from both presynaptic terminals and postsynaptic target neurons, we have recently demonstrated that Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) is capable of mobilizing synaptic vesicles from the reserved pool to the readily-releasable pool at different rates according to the patterns of inputs, and thus provides a key signaling element for dynamic gain control of synaptic strength. We are currently identifying the types of VGCCs involved in regulating neurotransmitter release and replenishment as well as downstream signaling targets and cascades (e.g. protein kinases, phosphatases, synaptic proteins) for Ca2+ to mobilize synaptic vesicles.
- Developmental properties of postsynaptic glutamate receptors.
The calyx of Held synapse undergoes profound morphological and functional modifications within the first two postnatal weeks. This time window covers synapse formation at about postnatal day 4-5 and the onset of functional hearing at postnatal day 10-12. The excitatory postsynaptic currents (EPSCs) increase dramatically in their size (3-5 fold) within this time frame and their decay time courses shorten markedly as well. In order to understand the mechanisms underlying such changes, we are investigating subunit composition of postsynaptic glutamate receptors and their density, clustering and gating behavior at different stages of development. We are also interested in studying how synaptic activity and neurotrophic factors influence developmental properties of glutamate receptors.
Future Research Interests
- To characterize and identify presynaptic voltage-gated ion channels.
- To determine Ca2+-dependent and -independent signaling cascades involved in regulating release and replenishment of synaptic vesicles.
- To define properties of postsynaptic glutamate receptors during early postnatal development.
- To investigate the effects of synaptic activity and neurotrophic factors on synaptic transmission.
- Canadian Institutes of Health Research (CIHR)
- Burroughs Welcome Fund (BWF)
- EJLB Foundation
- German Academic Exchange Service (DAAD) Faculty Visit Award (2006-2007)
- International Human Frontier Science Program Short-Term Fellowship (2006-2007)
- The Burroughs Wellcome Fund New Investigator Award (2001-2004)
- The EJLB Foundation Scholar Research Program Award (2000-2003)
- Canada Foundation for Innovation (CFI) New Opportunities Award (1998)
- CIHR New Investigator Scholarship (1998-2003)
Yang YM, Wang W, Fedchyshyn, MJ, Zhou Z, Ding JP and Wang LY. Enhancing the fidelity of neurotransmission by frequency-dependent facilitation of presynaptic K+ currents Nature Communication. 2014 Jul 31; 5:4564
David LS, Aitoubah J, Lesperance L, Wang LY. Gene delivery in mouse auditory brainstem and hindbrain using. Mol Brain. 2014 Jul 26;7(1):51.
Liu HW, Hou PP, Guo XY, Zhao ZW, Hu B, Li X, Wang LY, Ding JP, Wang S. Structural Basis for Calcium and Magnesium Regulation of a Large Conductance Calcium-activated Potassium Channel with Î²1 Subunits. J Biol Chem. 2014 Jun 13;289(24):16914-23.
Grande G, Negandhi J, Harrison RV, Wang LY. Remodelling at the calyx of Held-MNTB synapse in mice developing with unilateral conductive hearing loss. J Physiol. 2014 Apr 1;592(Pt 7):1581-600.
Wang W, Luo J, Hou P, Yang Y, Xiao F, Yuchi M, Qu A, Wang L, Ding J. Native gating behavior of ion channels in neurons with null-deviation modeling. PLoS One. 2013 Oct 25;8(10):e77105.
Grande G, Wang LY. Morphological and functional continuum underlying heterogeneity in the spiking fidelity at the calyx of Held synapse in vitro. J Neurosci. 2011 Sep 21;31(38):13386-99.
Yang YM, Aitoubah J, Lauer AM, Nuriya M, Takamiya K, Jia Z, May BJ, Huganir RL, Wang LY. GluA4 is indispensable for driving fast neurotransmission across a high-fidelity central synapse. J Physiol. 2011 Sep 1;589(Pt 17):4209-27.
Zhang B, Sun L, Yang YM, Huang HP, Zhu FP, Wang L, Zhang XY, Guo S, Zuo PL, Zhang CX, Ding JP, Wang LY, Zhou Z. Action potential bursts enhance transmitter release at a giant central synapse. J Physiol. 2011 May 1;589(Pt 9):2213-27.
Grande G, Wang LY. Early dating influences long-term synaptic partnerships. J Physiol. 2010 Nov 15;588(Pt 22):4339-40.
Xie G, Harrison J, Clapcote SJ, Huang Y, Zhang JY, Wang LY, Roder JC. A new Kv1.2 channelopathy underlying cerebellar ataxia. J Biol Chem. 2010 Oct 15;285(42):32160-73.
Yang YM, Fedchyshyn MJ, Grande G, Aitoubah J, Tsang CW, Xie H, Ackerley CA, Trimble WS, Wang LY. Septins Regulate developmental switching from microdomain to nanodomain coupling of Ca(2+) influx to neurotransmitter release at a central synapse. Neuron. 2010, 67:100-115.
Wang LY, Fedchyshyn MJ, Yang YM. Action potential evoked transmitter release in central synapses: insights from the developing calyx of Held. Mol Brain. 2009, 2:36.
Wang LY, Neher E, Taschenberger H. Synaptic vesicles in mature calyx of Held synapses sense higher nanodomain calcium concentrations during action potential-evoked glutamate release. J Neurosci. 2008, 28:14450-14458.
Tsang CW, Fedchyshyn M, Harrison J, Xie H, Xue J, Robinson PJ, Wang LY, Trimble WS. Superfluous role of mammalian septins 3 and 5 in neuronal development and synaptic transmission. Mol Cell Biol. 2008, 28:7012-7029.
Joshi I, Yang YM, Wang LY. 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. J. Neurosci. 2007, 27:9989-9999.
Fedchyshyn MJ, Wang LY. Activity-dependent changes in temporal components of neurotransmission at the juvenile mouse calyx of Held synapse. J. Physiol. (Lond.). 2007, 581:581-602.
Huang HP, Wang SR, Yao W, Zhang C, Zhou Y, Chen XW, Zhang B, Xiong W, Wang LY, Zheng LH, Landry M, Hökfelt T, Xu ZQ, Zhou Z. Long latency of evoked quantal transmitter release from somata. Proc. Natl. Acad. Sci. USA. 2007, 104:1401-1406.
Yang YM, Wang LY. Amplitude and kinetics of action potential evoked Ca2+ current and its efficacy in triggering transmitter release at the developing calyx of Held synapse. J. Neurosci. 2006, 26:5698-5708.
Wang LC, Xiong W, Zheng J, Zhou Y, Zheng H, Zhang C, Zheng LH, Zhu XL, Xiong ZQ, Wang LY, Cheng HP, Zhou Z. The timing of endocytosis after activation of a G-protein-coupled receptor in a sensory neuron. Biophys J. 2006, 90:3590-3598.
Fedchyshy, M.J. and Wang, L.-Y. Developmental transformation of release modality at a central synapse. J. Neurosci. 25:4131-4140 (2005)
Renden R., Taschenberger H., Puente N., Rusakov D.A., Duvoisin R., Wang L.-Y., Lehre K.P., and von Gersdorff H. Glutamate transporter studies reveal the pruning of mGluRs and absence of AMPA receptor desensitization at mature calyx of Held synapses. J. Neurosci. 25:8482-8497 (2005)
Joshi, I., Shahira Shokralla, Paul Titis and Wang, L.-Y., The role of AMPA receptor gating in the development of high fidelity neurotransmission at the calyx of Held synapse. J. Neurosci. 24, 183-196 (2004)
Joshi, I. and Wang, L.-Y., Developmental profiles of glutamate receptors and synaptic transmission at a single synapse in the mouse auditory brainstem. J. Physiol. (Lond.). 540, 861-873(2002)
Wang, L.-Y. The Dynamic Range for Gain control of NMDA Receptor-Mediated Synaptic Transmission at a Single Synapse. J. Neurosci. 20 (RC115), 1-5 (2000)
Wang, L.-Y., Gan, L., Forsythe, I.D. and Kaczmarek, L.K. Contribution of the Kv3.1 Potassium Channel to High Frequency Firing in Mouse Auditory Neurones. J. Physiol. (London) 509, 183-194 (1998)
Wang, L.-Y. and Kaczmarek, L.K. High Frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature 394, 384-388 (1998)
Wang, L.-Y., Orser, B.A., Brautigan, D.L. and MacDonald, J.F. Regulation of NMDA receptors in cultured hippocampal neurons by protein phosphatases 1 and 2A. Nature 369, 230-232 (1994)
Wang, L.-Y., Taverna, F.A., Huang, X-P., MacDonald, J.F. and Hampson, D.R. Phosphorylation and modulation of a kainate receptor (GluR6) by cAMP-dependent protein kinase. Science 259, 1173-1175 (1993)
Wang, L.-Y., Salter, M.W. and MacDonald, J.F. Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science 253, 1132-1135 (1991)