PiN Faculty Member - Michael Greenberg, PhD

Michael Greenberg, PhD

Nathan Marsh Pusey Professor of Neurobiology

Harvard Medical School
Department of Neurobiology
Goldenson Building, Room 420
220 Longwood Avenue
Boston, MA 02115
Tel: 617-432-2510
Fax: 617-432-3223
Visit my lab page here.

Our interactions with the outside world trigger changes at neuronal synapses that are critical for proper brain development and higher cognitive function. Research in the Greenberg laboratory has focused on the identification of a genetic program that is activated by neuronal activity, the mechanisms of signal transduction that carry the neuronal activity-dependent signal from the membrane to the nucleus, and the identification of regulators of this experience-dependent process that affect synapse development and plasticity. We are particularly interested in those activity-dependent processes whose dysfunction can lead to the development of diseases of cognitive function.

This work began in 1984 with the discovery that growth factors induce the rapid and transient expression of a family of genes, Immediate Early Genes (IEGs) such as c-fos, whose functions are crucial for neuronal differentiation, cell survival, and adaptive responses (Greenberg and Ziff, 1984). Our recent studies have used more global screening techniques to identify genes whose activity is regulated by stimuli such as membrane depolarization and calcium influx. For example, we recently employed genome-wide sequencing methods to discover thousands of neuronal activity-regulated distal enhancer elements that function in primary cortical cultures, providing new insights into the mechanism of stimulus-dependent enhancer function. From these and other studies we have identified a number of activity-dependent genes that control various processes such as 1) the complexity of the dendritic arbor, 2) the formation, maturation, and maintenance of spines, the post-synaptic sites of excitatory synapses, 3) the composition of protein complexes at the pre- and post-synaptic sites, and 4) 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 in the nervous system. 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.

Current research involves the integrated use of mouse models, traditional cell biological and biochemical methods and next generation sequencing technologies to analyze activity-dependent gene regulation and function. Laboratory projects include characterization of the function of various activity-responsive transcriptional regulators (e.g. Fos, Npas4, Creb) in diverse developmental contexts as well as the investigation of the roles of specific components of this activity-dependent transcriptional program that have been implicated in human disorders of cognitive function (e.g. Mecp2, Ube3a). These studies seek to both elucidate the mechanisms by which neuronal activity shapes the development of the central nervous system and provide new insight into the etiology of various human cognitive disorders.

Last Update: 9/16/2020


For a complete listing of publications click here.



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