Phone: 604 822-0398
Signaling and communication between cells is a pervasive and core issue in the biological sciences. Neurons in the mammalian brain accomplish these functions through a process known as synaptic transmission. It is known that the strength of synaptic transmission is not static but rather subject to dynamic regulation; plastic changes in synaptic strength are believed to be intimately associated with learning and memory, developmental refinement of neuronal circuitry, and the pathogenesis of a large number of brain disorders. Thus, understanding how the strength of synaptic transmission is controlled has been the subject of intense investigation and has been challenging neurobiologists for decades. The efficiency of synaptic transmission at any given synapse can be modified by altering the quantity of neurotransmitter released from the presynaptic terminal or by changing the activity of postsynaptic receptors. The goal of the long-term research program in my laboratory is to understand mechanisms controlling the efficacy of synaptic transmission via the regulation of postsynaptic receptors and the manner in which disease processes alter these mechanisms.
Study of the mechanisms governing membrane trafficking of postsynaptic ionotropic receptors is critical to our understanding of synaptic plasticity, and hence brain physiology and pathology. In particular, our research focus on excitatory amino acid (EAA) and type A gamma-aminobutyric acid (GABAA) receptors, given that these are the principal receptors mediating excitatory and inhibitory synaptic transmission in the brain. Expression of recombinant receptors in heterologous cell lines allows us to use various molecular techniques and characterize in detail the molecular mechanisms controlling the processes by which these receptors are trafficked. We then study these mechanisms in a physiological context by extending our results to neurons in primary dissociated cultures, brain slices, and the brains of animals as a function of behavior.
The goal of our research is, ultimately, to be able to treat central nervous disorders, such as cerebral ischemia and epilepsy, by designing new therapeutics which specifically target these receptors and their pathways.
Dong ZF, HL Han, HJ Li, YR Bai, W Wang, M Tu, Y Peng, LM Zhou, WT He, XB Wu, T Tan, MJ Liu, XY Wu, WH Zhou, WY Jin, S Zhang, T Sacktor, TY Li*, WH Song, and YT Wang, Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis, J. Clinical Investigation, 125(1): 234-247, 2015.
Fan X, WJ Jin, J Lu, J Wang, and YT Wang, Rapid and reversible knockdown of endogenous
proteins by peptide-directed lysosomal degradation, Nature Neurosci, 17(3):471-480, 2014.
Zhang S, C Taghibiglou, K Girling, Z Dong, SZ Lin, W Lee, WC Shyu, and YT Wang, Critical
role of increased PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries, J Neurosci, 33:7997-8008, 2013.
Xu, W, YC Tse, FA Dobie, M Baudry, AM Craig, TP Wong and YT Wang, Simultaneous monitoring of presynaptic transmitter release and postsynaptic receptor trafficking reveals an enhancement of presynaptic activity in metabotropic glutamate receptor-mediated long-term depression, J Neurosci, 33:5867-5877, 2013.
Dong Z, B Gong, H Li, Y Bai, X Wu, Y Huang, W He, T Li, and YT Wang, Mechanisms of hippocampal long-term depression are required for memory enhancement by novelty exploration, J Neurosci, 32:11980-11990, 2012.
Colligridge G, Peineau S, Howland JG and YT Wang, Long-Term Depression in the CNS, Nature Rev. Neurosci., 11:459-473, 2010.
Liu L, Wu DC and YT Wang, Allosteric potentiation of glycine receptor chloride channels by glutamate, Nature Neurosci., 13:1225-1235, 2010.
Lai T, and YT Wang, Fashioning drugs for stroke, Nature Medicine, 16:1376-1378, 2010.
Ge Y, ZF Dong, R Bagot, J Howland, A Phillips, TP Wong, and YT Wang, Hippocampal long-term depression is required for the consolidation of spatial memory, PNAS, 107:16697-16702, 2010.
Migues PV, O Hardt, DC Wu, K Gamache, T Sacktor, YT Wang and K Nader, PKMę maintains memories by regulating GluR2-dependent AMPA receptor trafficking, Nature Neuroscience, 13(5):630-636, 2010.
Martin HGS and YT Wang, Blocking the Deadly Effects of the NMDA Receptor in Stroke, Cell 140: 174-176, 2010.
Taghibiglou C, HGS Martin, TW Lai, T Cho, S Prasad, L Kojic, J Lu, Y Liu, E Lo, S Zhang, YP Li, JZZ Wu, YP Li, YH Wen, JH Imm, M Cynader and YT Wang, Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries, Nature Medicine, 15:1399-1406, 2009.
Bradley C, C Taghibiglou, GL Collingridge, YT Wang, Mechanisms involved in the reduction of GABAA receptor ?1 subunit expression caused by the epilepsy mutation A322D in the trafficking competent receptor, J. Biol. Chem. 283:22043-22050, 2008.
Wong TP, JG Howland, JM Robillard, Y Ge, W Yu, AK Titterness, K Brebner, L Liu, J Weinberg, BR Christie, AG Phillips, and YT Wang. Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment, Proc Natl Acad Sci, 104:11471-11476, 2007.
Liu Y, TP Wong, M Aarts, A Rooyakkers, L Liu, T Lai, DC Wu, J Lu, M Tymianski, AM Craig, YT Wang, NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo, J Neurosci, 27:2846-2857, 2007.
Brebner K, TP Wong, L Liu, Y Liu, P Campsall, S Gray, L Phelps, AG Phillips*, YT Wang* (*equal corresponding authors), Nucleus accumbens long-term depression and the expression of behavioral sensitization, Science,310:1340-1343, 2005.
Collingridge GL, JTR Isaac and YT Wang, Receptor trafficking and synaptic plasticity, Nature Neuroscience Rev.5:952-962, 2004.
Liu L, TP Wong, MF Pozza, K Lingenhoehl, Y Wang, M Sheng, YP Auberson, YT Wang, Subtypes of NMDA receptors govern the direction of hippocampal synaptic plasticity, Science, 304:1021-1024, 2004.
Wang QH, LD Liu, L Pei, W Ju, G. Ahmadian, J Lu, YS Wang, F Liu and YT Wang, Control of synaptic strength, a novel function of Akt, Neuron, 38:915-928, 2003.
Nong Y, YQ Huang, W Ju, LV Kalia, G Ahmadian, YT Wang*, MW Salter* (*equal corresponding authors), Glycine binding primes NMDA receptor internalization, Nature, 422:302-307, 2003.