Neurons are destroyed according to patterns of selective vulnerability in the neurodegenerative diseases. However, we know very little about what specific mechanisms cause one neuron to be more vulnerable to the disease process than the next. In several of these disease glutamate-mediated "excitotoxic" cell death may play an important role. Furthermore, much has been recently learned about the specific molecular structure and physiology of the glutamate receptor subunits. I am interested in relating the expression patterns of glutamate receptor subunits in specific neurons to their selective vulnerability to glutamate-mediated cell death. Such relationships can only be elucidated by the combination of methods which assay molecular expression of individual subunits with methods studying functional properties of the receptors which form. I employ patch-clamp and [Ca2+]i-microfluorimetic methods to study functional properties of expressed glutamate receptors, fluorescence assays to study toxicity, and molecular methods such as PCR and Southern blotting to study expression patterns of glutamate receptor subunits, applied to neurons growing in primary dissociated cultures. 

Initial studies focused on cerebellar Purkinje cells, which lack functional NMDA receptors, have shown that AMPA receptors mediate excitotoxicity, and that the unusual pattern of AMPA subunit splice variant expression in these cells may explain their selective vulnerability. Other work examines hippocampal pyramidal neurons, studying the secondary mediators of Ca2+-dependent toxicity such as nitric oxide. Finally, we are also investigating the mechanisms by which the protein deposited in Alzheimer's disease, beta-amyloid protein, might be toxic to neurons. If we can understand the specific mechanisms of neuronal degeneration occurring in individual neuronal types, we can better plan appropriate interventions in diseases in which these neurons die. 

 Brorson, J.A. and Zhang, H. (1997) Disrupted [Ca²⁺]_i homeostasis contributes to the toxicity of nitric oxide in cultured hippocampal neurons. J Neurochem, 69:1882-1889. 

James R. Brorson, Zehui Zhang and Wim Vandenberghe; "Ca2+ permeation of AMPA receptors in cerebellar neurons expressing Glu receptor 2." Journal of Neuroscience, 19:9149-9159 (1999).

Wim Vandenberghe, Wim Robberecht, and James R. Brorson; "AMPA receptor calcium permeability, Glu receptor 2 expression, and selective motoneuron vulnerability." Journal of Neuroscience, 20:123-132 (2000).

Emin Maltepe, Brian Keith, Andrew M. Arsham, James R. Brorson, and M. Celeste Simon; "The role of ARNT2 in tumor angiogenesis and the neuronal response to hypoxia." Biochemical and Biophysical Research Communications273: 231-238 (2000).

Wim Vandenberghe, Eva C. Ihle, Doris K. Patneau, Wim Robberecht, and James,R. Brorson; "AMPA receptor current density, not desensitization, predicts selective motoneuron vulnerability." Journal of Neuroscience, 20:7158-7166 (2000).

Wim Vandenberghe, Vytautas P. Bindokas, Richard J. Miller, Wim Robberecht, and James R. Brorson; "Subcellular localization of calcium-permeable AMPA receptors in spinal motoneurons."  European Journal of Neuroscience, 14:305-314 (2001).