Paul Rosenberg, M.D., Ph.D.

Associate Professor of Neurology

Kirby Neurobiology Center
Children's Hospital
Center for Life Science Building
3 Blackfan Circle
Boston, MA 02115
Telephone: 617-355-6962
Fax: 617- 730-0243
Email: paul.rosenberg@childrens.harvard.edu
Lab Website: The Rosenberg Lab

We are studying the function, regulation, and expression of glutamate transporters in the brain.  Glutamate transport is important in the physiology of excitatory synapses and for the survival of neurons and oligodendrocytes because of the phenomenon of excitotoxicity.  We recently demonstrated that the glutamate transporter GLT1 is the major glutamate transporter in excitatory terminals, and now we are interested in determining the contribution of presynaptic glutamate transport to the function of excitatory synapses and to the pathophysiology of neurodegenerative diseases, in particular, Huntington’s disease.  Approaches include yeast 2-hybrid studies seeking protein interactors, patch-clamp recording of glutamate currents from neurons, astrocytes, and cell lines expressing glutamate transporters, to characterize the biophysical properties of glutamate transporters, and knockouts to investigate the role of presynaptic GLT1 expression in learning and memory and excitotoxic injury.

In the second area of interest, we are studying the molecular mechanisms by which oxidative stress and excitotoxicity produce cell death in neurons and oligodendrocytes, and the role of these mechanisms in the pathogenesis of neuron and oligodendrocyte injury in cerebral palsy, stroke, Huntington’s disease, and amyotrophic lateral sclerosis.  Tissue culture models of oxidative stress-, excitotoxin-, and cytokine-evoked cell death are currently under investigation.

Finally, another project is focused on the mechanisms underlying the control of behavioral state.  We are particularly interested in the roles of nitric oxide and adenosine.  We have found that the response to sleep deprivation (recovery sleep) is due to the production of nitric oxide by inducible nitric oxide synthase in the basal forebrain.  The major questions emerging from this work include: which cells express iNOS, what activates iNOS expression in these cells, what is the molecular pathway activated by release of nitric oxide and in what cells does the activation occur, and how is REM recovery sleep regulated?

References:

• Deng, W. Neve, R.L. Rosenberg, P.A. Volpe, J.J. Jensen, F.E. AMPA receptor subunit composition and CREB regulate oligodendrocyte excitotoxicity. J Biol Chem 2006; 281: 36004-36011.
• Deng, W. Yue, Q. Rosenberg, P.A. Volpe, J.J. Jensen, F.E. Oligodendrocyte excitotoxicity determined by local glutamate accumulation and mitochondrial function. J Neurochem 2006; 98:213-222.
• Zhang, Y. Wang, H. Dong, L. Xu, P. Chen, W. Neve, R.L. Volpe, J.J. Rosenberg, P.A. Intracellular zinc release and ERK phosphorylation are required upstream of 12-lipoxygenase activation in peroxynitrite toxicity to mature rat oligodendrocytes. J Biol Chem 2006; 281: 9460-9470.
• Redman, P.T. He, K. Hartnett, K.A. Jefferson, B.S. Hu, L. Rosenberg, P.A. Levitan, E.S. Aizenman, E. Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1. Proc Natl Acad Sci USA 2007;104: 3568-3573.
• DeSilva, T.M. Kinney, H.C. Borenstein, N.S. Trachtenberg, F.L. Irwin, N. Volpe, J.J. Rosenberg, P.A. . The glutamate transporter EAAT2 is transiently expressed in developing human cerebral white matter. J Comp Neurol 2007;501: 879-890.
• Gerstner, B. Sifringer, M. Dzietko, M. Schuller, A. Lee, J. Simons, S. Obladen, M. Volpe, J.J. Rosenberg, P.A. Felderhoff-Mueser, U. Estradiol attenuates hyperoxia-induced cell death in the developing white matter. Ann Neurol 2007;61: In Press.

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