陈功

Neurodevelopment and Neurodegeneration

My lab employs multidisciplinary approaches, including molecular biology, fluorescence imaging, electrophysiology, immunocytochemistry, biochemistry, and electron microscopy to study the molecular mechanisms of brain development and neurodegenerative disorders. We are currently  developing stem cell therapy for the treatment of neurological disordes.

How brain circuit is established and regulated to carry out complex functions is the most fascinating question in neuroscience research. Many neurological disorders are due to improper formation of neural circuits. My lab investigates the molecular and cellular mechanisms of synapse formation and synaptic plasticity, with a special focus on GABAergic synapse in the developing brain. GAGA signaling emerges very early during embryonic brain development. GABA function changes from excitation in immature neurons to inhibition in mature neurons. We previously have investigated GABAergic function during epileptogenesis and established a novel chemical-induced epilepsy model. Recently, we are studying GABAergic deficits in psychiatric disorders, including autism and schizophrenia. We are also starting to use stem cells, including induced pluripotent stem cells (iPSCs), to model neurological disorders and to study GABA regulation of stem cell development.

Neurodegenerative disorders afflict millions of people worldwide and have become an enormous socioeconomic burden for society. Our goal is to develop an effective therapy to reduce or alleviate the symptoms and help patients live an independent life. Our strategy is centered on synapses because synaptic loss is the first step leading to neurodegeneration. We are investigating the molecular mechanisms underlying synaptic loss during neurodegeneration, with an emphasis on synaptic deficits induced by cytoskeleton protein aggregation. We are also developing a neural stem cell therapy, including using iPSCs to treat neurodegenerative disorders.

Wu X, Wu Z, Ning G, Guo Y, Ali R, Macdonald RL, De Blas AL, Luscher B, Chen G.  (2012)   gamma-Aminobutyric Acid Type A (GABAA)  Receptor Alpha Subunits Play a Direct Role in Synaptic versus Extrasynaptic Targeting.      J Biol Chem.  287(33): p. 27417-27430.    (Paper of the Week)        News coverage:  http://www.sciencedaily.com/releases/2012/08/120808093854.htm

  Joseph Cichon, Chi-Cheng Sun, Ben Chen, Min Jiang, Xiangyun Amy Chen, Yajie Sun, Yun Wang^*, and Gong Chen^*.   (2012)  Cofilin Aggregation Blocks Intracellular Trafficking and Induces Synaptic Loss.J Biol Chem.  287(6): 3919–3929.  

  Brennand, K., A. Simone, J. Jou, C. Gelboin-Burkhart, N. Tran, S. Sangar, Y. Li, Y. Mu, G. Chen, D. Yu, S. McCarthy, J. Sebat, and F. Gage. (2011)  Modeling schizophrenia using human induced pluripotent stem cells. Nature 473: 221-225.

  Sun, C., M.-C. Cheng, R. Qin, D.L. Liao, T.-T. Chen, F.-J. Koong, G. Chen*, and C.-H. Chen*. (2011)  Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Human Molecular Genetics, 20(15): 3042–3051.

  Fan, Y., X. Tang, E. Vitriol, G. Chen, and J. Q. Zheng. (2011)  Actin capping protein is required for dendritic spine development and synapse formation. Journal of Neuroscience 31(28): 10228-10233.

  Yazhou Sun, Yaqiong Wang, Yi Hu, Gong Chen, Hong Ma.  (2011).   Comparative analysis of neural transcriptomes and functional implication of unannotated intronic expression.  BMC Genomics, 2011 Oct 10;12:494.

  Marchetto, M. C. N., C. Carromeu, A. Acab, D. Yu, G. Yeo, Y. Mu, G. Chen, F. H. Gage, and A. R. Muotri.  (2010)  A model for neural development and treatment of Rett Syndrome using human induced pluripotent stem cells. Cell 143: 527-539.

  Gu, J., C. W. Lee, Y. Fan, D. Komlos, X. Tang, C. Sun, K. Yu, H. C. Hartzell, G. Chen, J. R. Bamburg, and J. Q. Zheng.  (2010)  ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nature Neuroscience 13: 1208-1215.

  Kong S, Qian B, Liu J, Fan M, Chen G, Wang Y.   (2010).   Cyclothiazide induces seizure behavior in freely moving rats.   Brain Res. 1355:207-213.

  Han, X. W., X. Wu, W. Y. Chung, T. Li, A. Nekrutenko, N. S. Altman, G. Chen*, and H. Ma*.  (2009)  Transcriptome of embryonic and neonatal mouse cortex by high-throughput RNA sequencing. Proc.Nat. Acad. Sci. USA 106: 12741-12746.

  Jiang, M. and G. Chen.   (2009)   Ca2+ regulation of dynamin-independent endocytosis in cortical astrocytes. Journal of Neuroscience 29: 8063-8074.

  Wang, Y., J. S. Qi, S. Kong, Y. Sun, J. Fan, M. Jiang, and G. Chen.   (2009)   BDNF-TrkB signaling pathway mediates the induction of epileptiform activity induced by a convulsant drug cyclothiazide. Neuropharmacology 57: 49-59.

  Yuan, X., J. Yao, D. Norris, D. D. Tran, R. J. Bram, G. Chen, and B. Luscher.   (2008)   Calcium-modulating cyclophilin ligand regulates membrane trafficking of postsynaptic GABA(A) receptors. Mol. Cell Neurosci. 38(2): 277-289.

  Deng, L., J. Yao, C. Fang, N. Dong, B. Luscher, and G. Chen.   (2007)  Sequential postsynaptic maturation governs the temporal order of GABAergic and glutamatergic synaptogenesis in rat embryonic cultures. Journal of Neuroscience 27(40): 10860-10869.

  Dong, N., Qi, J., Chen, G.   (2007).   Molecular reconstitution of functional GABAergic synapses with expression of neuroligin-2 and GABA_A receptors.        Mol. Cell. Neurosci. 35: 14 - 23.

  Wendou Yu, Min Jiang, Celia P. Miralles, Gong Chen and Angel L. de Blas.  (2007). Gephyrin clustering is required for the stability of GABAergic synapses. Mol. Cell. Neurosci.   36(4):484-500.     

  Fang, C., Deng, L., Keller, C., Fukata, M., Fukata, Y., Chen, G., and Lüscher, B.   (2006). GODZ-mediated palmitoylation of GABA_A receptors is required for normal assembly and function of GABAergic inhibitory synapses. Journal of Neuroscience 26(49): 12758-12768 .

  Qi, J. S., Yao, J., Fang, C., Lüscher, B., and Chen, G.  (2006).  Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures. Journal of Physiology 577(2): 579-590.

  Yao, J., Qi, J. S., and Chen, G.  (2006).  Actin-dependent activation of presynaptic silent synapses contributes to long-term synaptic plasticity in developing hippocampal neurons. Journal of Neuroscience, 26 (31): 8137 – 8147.

  Jiang, M. and Chen, G.   (2006).   High Ca²⁺-phosphate transfection efficiency in low-density neuronal cultures.  Nature Protocols. Vol. 1. (No. 2) 695 – 700. (Invited article)

  Qi, J.S., Wang, Y., Jiang M., Warren, W., and Chen, G.  (2006). Cyclothiazide induces robust epileptiform activity in rat hippocampal neurons both in vitro and in vivo. Journal of Physiology  571(3): 605-618.

  Zhou, J., Pfaff, D. W., and Chen, G. (2005). Sex differences in estrogenic regulation of neuronal activity in neonatal cultures of ventromedial nucleus of the hypothalamus. PNAS 102: 14907-14912.  

  Alldred, M.J., Mulder-Rosi, J., Lingenfelter, S. E., Chen, G., and Lüscher, B.  (2005) Distinct g2 Subunit Domains Mediate Clustering and Synaptic Function of Postsynaptic GABA_A Receptors and Gephyrin. Journal of Neuroscience 25(3): 594-603.  

  Jiang, M., Deng, L.B., and Chen, G.   (2004).  High Ca²⁺-phosphate transfection efficiency enables single neuron gene analysis.  Gene Therapy  11:1303-1311.  

  Cao, Y-Q., Piedras-Renteria, E., Smith, G. B., Chen, G., Harata, N. C., Tsien, R. W.   (2004). Presynaptic Ca²⁺ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca²⁺ channelopathy. Neuron 43: 387-400.  

  Chen, G., Harata, N. and Tsien, R. W.  (2004). Paired-pulse depression of unitary quantal amplitude at single hippocampal synapses. PNAS 101: 1063-1068.   

Deng, L. B., and Chen, G. (2003). Cyclothiazide potently inhibits g-aminobutyric acid type A receptors in addition to enhancing glutamate responses. PNAS 100 (22): 13025-13029.   

 Chen, Y., Deng, L. B., Maeno-Hikichi, Y., Lai, M. Z., Chang, S. H., Chen, G., and Zhang, J. F. (2003). Formation of an endophilin-Ca²⁺ channel complex is critical for clathrin-mediated synaptic vesicle endocytosis. Cell 115: 37-48.