Michael E. Greenberg

Chair, Department of Neurobiology
Harvard Medical School
Goldenson Building, Room 420
220 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-2510
Fax: (617) 432-3223
Email: meg@hms.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:

Lin Y, Hauser JL, Bloodgood BL, Lapan AD, Koon AK, Kim TK, Hu LS, Malik AN, Greenberg ME. Activity-dependent regulation of GABAergic synapse development by Npas4. Nature 2008 Oct 30;455(7217): 1198-204.
Hong EJ, McCord AE, Greenberg ME. A biological function for the neuro activity-dependent component of Bdnf transcription in the development of cortical inhibition. Neuron 2008;60(4); 610-624.
Flavell SW, Kim TK, Gray JM, Harmin DA, Hembeg M, Hong EJ, Markenscoff-Papdimitriou E, Bear DM, Greenberg ME. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 2008; 60(6): 1022-1038.
Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, Harmin DA, Laptewicz M, Barbara-Haley K, Kuersten S, Markenscoff-Papadimitriou E, Kuhl D, Bito H, Worley PF, Kreiman G, Greenberg ME. Widespread transcription at neuronal activity-regulated enhancers. Nature. 2010 Apr 14.
Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim TK, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME. The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell. 2010 Mar 5;140(5):704-16.
Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S, Jung C, Hu L, Mok SI, Shah A, Savner EM, Tolias C, Corfas R, Chen S, Inquimbert P, Xu Y, McInnes RR, Rice FL, Corfas G, Ma Q, Woolf CJ, Greenberg ME. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron. 2010 Mar 25;65(6):886-98.

BBS webpage updated 5/18/2010