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Lu-Yang Wang

Research Interests

• Excitatory synaptic transmission
• Voltage-gated calcium and potassium channels
• Neurotransmitter release and replenishment
• Glutamate receptors
• Neurotrophic ractors
• Auditory brainstem

Research Activities

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.

External Funding

• Canadian Institutes of Health Research (CIHR)
• Burroughs Welcome Fund (BWF)
• EJLB Foundation

Achievements

• 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)

Publications

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.

Renden R, Taschenberger H, Puente N, Rusakov DA, Duvoisin R, Wang LY, Lehre KP, von Gersdorff H. Glutamate transporter studies reveal the pruning of metabotropic glutamate receptors and absence of AMPA receptor desensitization at mature calyx of held synapses. J Neurosci. 2005, 25:8482-8497.

Fedchyshyn MJ, Wang LY. Developmental transformation of the release modality at the calyx of held synapse. J Neurosci. 2005, 25:4131-4140.

Joshi I, Shokralla S, Titis P, Wang LY. The role of AMPA receptor gating in the development of high-fidelity neurotransmission at the calyx of Held synapse. J Neurosci. 2004, 24:183-96.

Ming G, Wang LY. Properties of voltage-gated sodium channels in developing auditory neurons of the mouse in vitro. Chin Med Sci J. 2003, 18:67-74.

Macica CM, von Hehn CA, Wang LY, Ho CS, Yokoyama S, Joho RH, Kaczmarek LK. Modulation of the kv3.1b potassium channel isoform adjusts the fidelity of the firing pattern of auditory neurons. J Neurosci. 2003, 23:1133-1141.

Joshi I, Wang LY, Developmental profiles of glutamate receptors and synaptic transmission at a single synapse in the mouse auditory brainstem. J. Physiol. (Lond.). 2002, 540, 861-873.

Wang LY. The dynamic range for gain control of NMDA receptor-mediated synaptic transmission at a single synapse. J. Neurosci. 2000, 20 (RC115), 1-5.

Smith TC, Wang LY, Howe JR. Heterogeneous conductance levels of native AMPA receptors. J. Neurosci. 2000, 20, 2073-2085.

Smith TC, Wang LY, Howe JR. Distinct kainate receptor phenotypes in immature and mature mouse cerebellar granule cells. J. Physiol. (London), 1999, 517, 51-58.

Joiner WJ, Tang MD, Wang LY, Dworetzky SI, Boissard CG, Gan L, Gribkoff VK, Kaczmarek LK. Formation of intermediate conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nature Neurosci. 1998, 1, 462-469.

Wang LY, Kaczmarek LK. High frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature, 1998, 394: 384-388.

Wang LY, Gan L, Perney TM, Schwartz I, Kaczmarek LK. Activation of Kv3.1 channels in neuronal spine-like structures may induce local potassium ion depletion. Proceedings of the National Academy of Science USA, 95: 1882-1887, 1998.

Wang LY, Gan L, Forsythe ID, Kaczmarek LK. Contribution of the Kv3.1 potassium channel to high frequency firing in mouse auditory neurones. Journal of Physiology, 1998, 509: 183-194.

Wang LY, MacDonald JF. Modulation by magnesium of the affinity of NMDA receptors for glycine in murine hippocampal neurons. Journal of Physiology, 1995, 486: 83-95.

Wang LY, Orser BA, Brautigan DL, MacDonald JF. Regulation of NMDA receptors in cultured hippocampal neurons by protein phosphatases 1 and 2A. Nature, 1994, 369: 230-232.

Wang LY, Taverna FA, Huang XP, MacDonald JF, Hampson, DR. Phosphorylation and modulation of a kainate receptor (GluR6) by cAMP-dependent protein kinase. Science, 1993, 259: 1173-1175.

Wang LY, Salter MW, MacDonald JF. Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science. 1991, 253: 1132-1135.