Lu Chen博士简介

生物谷

Lu Chen

Assistant Professor of Neurobiology
*and Member of the Helen Wills Neuroscience Institute

E-mail: luchen@berkeley.edu
Phone: (510) 643-8163

Full Directory Information

Research Interests

We are interested in the mechanisms of synapse formation during development and synapse modification in plasticity. In particular, we aim to decipher protein composition of the synapse and understand how interactions among these proteins support and regulate synapse function.

Current Projects

At postsynaptic specializations, neurotransmitter receptors are clustered and tethered down by a large array of synaptic proteins. By focusing on the glutamate receptor family, we are attempting to understand the mechanisms of receptor targeting during synapse formation and plasticity. The life of a glutamate receptor involves its synthesis in ER, sorting through the Golgi network, insertion into the plasma membrane, targeting to synapses, internalization into endosomes, recycling to surface, and eventually, degradation in lysosomes. In the case of AMPA receptors, a number of receptor-interacting PDZ proteins, such as GRIP, ABP, PICK1, SAP-97 and Stargazin/PSD-95, have been implicated in different steps of these processes. However, a clear delineation of a role for each protein at a given step of AMPA receptor trafficking has not been achieved. By combining biochemical and electrophysiological approaches and using Xenopus oocytes as well as organotypic slice culture preparations, we hope to uncover the molecular mechanisms of receptor trafficking.

An ultimate test to our knowledge of the synapse is to actually build one. When transfected into non-neuronal cells, synaptic adhesion molecules (such as neuroligin) are able to induce morphological and functional presynaptic differentiation and form a synapse-like structure with passing axons from co-cultured pontine explants. Our goal is to use this system to build a postsynaptic structure. We have found that when AMPA receptor subunits, PSD-95 and stargazin are co-transfected into HEK cells, they form distinctive patch-like surface clusters that are not observed when only two of the three proteins are introduced. Importantly, neuroligin, the key molecule for inducing presynaptic innervations and transmitter release, also binds to PSD-95. Taken together, these findings suggest that if we transfect AMPA receptor subunits, PSD-95, stargazin and neuroligin together into HEK cells, the AMPA receptors may preferentially cluster at sites opposing differentiated presynaptic terminals originating from nearby pontine explants, forming an "artificial synapse." We are establishing such a system and examining its structural and electrophysiological properties. The postsynaptic proteins introduced will not be limited to the onesmentioned above. Cell lines that stably express a number of essential proteins (i.e. neuroligin, PSD-95 and GluR1) will be established to enhance the feasibility of introducing additional proteins. Once a rudimentary synapse is constructed, we will be able to study receptor-synaptic protein interaction from a new angle - putting the synapse together, one piece at a time.

Selected Publications

Stargazin differentially controls the trafficking of AMPA and kainate receptors. [L. Chen, A. El-Husseini, A. Tomita, D. S. Bredt and R. A. Nicoll Molecular Pharmacology 64, 703-706]

Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. [S. Tomita, L. Chen, Y. Kawasaki, R. S. Petralia, R. J. Wenthold, R. A. Nicoll and D. S. Bredt (2003)J. Cell Bio. 161, 805-816]

Phosphorylation of the PDZ Binding Site of Stargazin Regulates Binding to PSD-95 and Synaptic Targeting of AMPA Receptors. [L. Chen, D. M. Chetkovich, T. J. Stocker, R. A. Nicoll and D. S. Bredt (2002) J. Neurosci. 22, 5791-5796]

Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. [L. Chen, D. M. Chetkovich, R. S. Petralia, N. Sweeney, Y. Kawaski, R. J. Wenthold, D. S. Bredt and R. A. Nicoll (2000) Nature 408, 936-943]

Genetic substrates of memory: cerebellum [S. Bao and L. Chen (2001). In Encyclopedia of Learning and Memory, 2nd edition (Ed. J. H. Byrne) MacMillan, Farmington Hills]

Impaired cerebellar synapse maturation in waggler, a mutant mouse with a disrupted neuronal calcium channel gamma subunit. [L. Chen, S. Bao, X. Qiao and R. F. Thompson (1999) Proceedings of the National Academy of Sciences of the United States of America 96, 12132-12137]

Impaired classical eyeblink conditioning in cerebellar lesion and Purkinje cell degeneration mutant mice. [L. Chen, S. Bao, J. J. Kim, J. Lockard and R. F. Thompson (1996) J. Neurosci. 16, 2829-2838]

Last Updated 8/20/2004