Our laboratory combines molecular, cellular, and electrophysiological approaches with state-of-art Expansion Microscopy and 3D electron microscopy in the cultured neuron and transgenic mouse models to analyze how neurons establish their communications through a specialized unit termed “synapse”. We are particularly interested in an interdisciplinary study about the role of extracellular polysaccharide in regulating the structure and function of synapses. Elucidating these mechanisms is important for understanding how synapses develop in health and how they dysfunction in neurodevelopmental and neurodegenerative disorders.
The human brain is made up of billions of neurons that connect precisely through 100 trillion+ specialized junctions called synapses. If a brain is considered a dedicated computer, synapses are the nodes relaying information from neurons to other targets. These synapses are tiny in size (<100 nm mostly) but enormously complex and diverse in their molecular composition, structural morphology and physiological properties. So, synapses are distinct in different brain circuits where distinct behaviors are executed.
Fascinated by the complexity and diversity of synapses, we strive to understand the molecular codes behind them. The obvious candidates for establishing such codes are a group of synaptic organizing proteins that mediates specific synaptic recognition and differentiation between two neurons. The diversity of proteins is expanded by different isoforms created by alternative mRNA splicing. Yet how post-translational modifications upon the synaptic organizing proteins contribute to the complexity remains largely unexplored. We recently discovered an evolutionarily conserved glycosylation (heparan sulfate polysaccharides) on the core synaptic organizing protein neurexin. Then we defined the functional requirement of this glycan for the normal synaptic structure and function. Now, our lab aims to elucidate how glycans increase the complexity of molecular codes governing synaptic specificity and diversity.
Multiple model systems are adopted to address our questions, such as cultured neurons and transgenic mice. A wide range of interdisciplinary techniques are applied, including but not limited to molecular biology, biochemistry, electrophysiology and mouse behavioral observation. In particular, we have set up the methods of sub-diffraction fluorescence-imaging and serial block-face scanning electron microscopy. These robust tools allow us to analyze the molecular architecture and structural morphology of synapses at nanoscale. Combining our expertise in glycobiology and synapse development, we expect to gain insights to how glycan-based molecular processes govern synapse development and provide a foundation for deriving novel therapeutic approaches to correct imbalances in the synaptic pathway in neuropsychiatric disorders.
The Zhang Lab is looking for motivated undergraduate and graduate students and postdoctoral fellows. All interested candidates are encouraged to contact Peng with a detailed CV and cover letter
Awards and Honors
Zhang, P.#, Lu, H., Peixoto, R.T., Pines, M.K., Ge, Y., Oku, S., Siddiqui, T.J., Xie, Y., Wu, W., Archer-Hartmann, S., Yoshida, K., Tanaka, K.F., Aricescu, A.R., Azadi, P., Gordon, M.D., Sabatini, B.L., Wong, R.O.L. and Craig, A.M.# (2018) Heparan Sulfate Organizes Neuronal Synapses Through Neurexin Partnerships. Cell. 174, 1450-1464 e1423,. (#Corresponding authors) [Previewed in Cell and highlighted by Faculty of 1000]
Li, Y.*, Zhang, P.*, Choi, T.Y., Park, S.K., Park, H., Lee, E.J., Lee, D., Roh, J.D., Mah, W., Kim, R., et al. (2015). Splicing-Dependent Trans-synaptic SALM3-LAR-RPTP Interactions Regulate Excitatory Synapse Development and Locomotion. Cell Rep 12, 1618-1630. (*These authors Contributed equally)
Zhang, P., and Craig, A.M. (2015). Inhibitory Synapses Get Madd for Neuroligin. Neuron 86, 1321-1324.
Coles, C.H., Mitakidis, N., Zhang, P., Elegheert, J., Lu, W., Stoker, A.W., Nakagawa, T., Craig, A.M., Jones, E.Y., and Aricescu, A.R. (2014). Structural basis for extracellular cis and trans RPTPsigma signal competition in synaptogenesis. Nat Commun 5, 5209.
Siddiqui, T.J., Tari, P.K., Connor, S.A., Zhang, P., Dobie, F.A., She, K., Kawabe, H., Wang, Y.T., Brose, N., and Craig, A.M. (2013). An LRRTM4-HSPG complex mediates excitatory synapse development on dentate gyrus granule cells. Neuron 79, 680-695. [Highlighted in neuron]
Zhang, P., Yang, Y., Candiello, J., Thorn, T.L., Gray, N., Halfter, W.M., and Hu, H. (2013). Biochemical and biophysical changes underlie the mechanisms of basement membrane disruptions in a mouse model of dystroglycanopathy. Matrix Biol 32, 196-207
Zhang, P., and Hu, H. (2012). Differential glycosylation of alpha-dystroglycan and proteins other than alpha-dystroglycan by like-glycosyltransferase. Glycobiology the Official Journal of the Society for Glycobiology 22, 235-247.
Zhang, Z.*, Zhang, P.*, and Hu, H. (2011). LARGE expression augments the glycosylation of glycoproteins in addition to alpha-dystroglycan conferring laminin binding. PLoS One 6, e19080. (*These authors Contributed equally)