Biological and Biomedical Science
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Michael E. Greenberg

Department of Neurobiology
Children's Hospital
Neurobiology Program
Enders Building, Room 250
320 Longwood Avenue
Boston, MA 02115
Tel: (617) 355-8344
Fax: (617) 730-0242
Email: michael.greenberg@childrens.harvard.edu
Web Page: The Greenberg Lab Page

Our experiences and interactions with the world trigger changes at neuronal synapses that are critical for proper brain development and higher cognitive function. The Greenberg laboratory is interested in the identification of a genetic program that is activated by such neuronal activity, the mechanism of signal transduction that carries this signal from the membrane to the nucleus, and the identification of regulators of this experience-dependent process that affect synapse development, refinement and plasticity. Because of the central role that these proteins play in establishing the proper circuitry of the brain, mutations in these proteins can lead to the development of diseases of cognitive function.

Our approach has been to use primary neuronal cultures and to trace the signal “in reverse” from the transcription of a particular activity-dependent gene back to the original signal at the membrane. Our recent studies have used more global screening techniques to identify genes whose activity is regulated by various extra-cellular stimuli, to determine how these genes are regulated, and to study the function of these gene products. From these studies we have identified a number of activity-dependent genes that control processes such as 1) the complexity of the dendritic arbor, 2) the formation, maturation, remodeling and maintenance of spines, the post-synaptic sites of excitatory synapses, 3) the composition of protein complexes at the pre- and post-synaptic sites, 4) the local regulation of protein translation at the synapse by micro-RNAs, and 5) the relative number of excitatory and inhibitory synapses.

Many disorders of human cognition, including various forms of mental retardation and autism, are correlated with changes in the number of synapses or are believed to be caused by an imbalance between neuronal excitation and inhibition. Thus, understanding how the neuronal activity-dependent gene program functions may provide insight into the molecular mechanisms that govern synaptic development and ultimately, how the deregulation of this process leads to neurological diseases.

 

References:

  • Flavell, S. W., Cowan, C. W., Kim, T. K., Greer, P. L., Lin, Y., Paradis, S., Griffith, E. C., Hu, L. S., Chen, C., Greenberg, M. E. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 2006, 311 (5763): 1008.
  • Zhou, Z., Hong, E. J., Cohen, S., Zhao, W. N., Ho, H. Y., Schmidt, L., Chen, W. G., Lin, Y., Savner, E., Griffith, E. C., Hu, L., Steen, J. A., Weitz, C. J., Greenberg, M. E. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 2006, 52 (2): 255.
  • Paradis, S., Harrar, D. B., Lin, Y., Koon, A. C., Hauser, J. L., Griffith, E. C., Zhu, L., Brass, L. F., Chen, C., Greenberg, M. E. An RNAi-based approach identifies molecules required for glutamatergic and GABAergic synapse development. Neuron 2007, 53 (2): 217.
  • Ma YC, Song MR, Park JP, Ho HH, Hu L, Kurtev M, Zieg J, Ma Q, Pfaff SL, Greenberg ME. Regulation of motor specification by phosphorylation of Ngn2. Neuron 2008 April 10; 58(1):65-77