Robert J. Wenthold, Ph.D.

Chief
Laboratory of Neurochemistry

Chief
Section on Neurotransmitter Receptor Biology
Laboratory of Neurochemistry

Dr. Wenthold received a B.S. degree from Loras College and his Ph.D. from Indiana University where he worked with Henry Mahler on the biochemistry of synaptic proteins. After postdoctoral work at the NIH with Jorgen Fex, he became a faculty member in the Department of Neurophysiology at the University of Wisconsin. He joined NINCDS as a Senior Investigator in 1984 and moved to NIDCD when the institute was created in 1989. He became Chief of the Laboratory of Neurochemistry in 1996 and Scientific Director of NIDCD in 1998. Dr. Wenthold's laboratory studies the assembly, trafficking and synaptic expression of glutamate receptors.

Research Statement

The Section on Neurotransmitter Receptor Biology studies the molecular mechanisms underlying the regulation of glutamate receptors at the synapse. This complex family of proteins mediates most excitatory neurotransmission in the central nervous system and has been shown to play a direct role in some forms of synaptic plasticity that may be associated with learning and memory. Our current research is focused on three areas: (1) Assembly of receptor complexes. Ionotropic glutamate receptors are formed by the assembly of several subunits into a complex of 4 or 5 subunits. Multiple complexes of different subunit configurations are found within the same neuron, and these complexes can be targeted to different populations of synapses. We are interested in determining how these different complexes are produced and the factors that may alter their production. (2) Delivery of receptors to the synapse. We are interested in how receptors are selectively trafficked through the various cellular compartments to their appropriate synaptic location. This includes the identification of proteins that interact with the receptors during this delivery and the modifications to the receptor that may alter this delivery. (3) Stabilization of receptors at the synapse. Receptors are concentrated at the postsynaptic membrane probably through an interaction with proteins of the postsynaptic density. We are interested in the identity of these proteins and how these interactions are regulated. Removal of receptors from the synapse through internalization is likely to involve a disruption of the association with the anchoring protein. Our research involves primarily molecular techniques but relies heavily on morphological and physiological approaches. Immunogold electron microscopy, confocal microscopy, and cell culture complement our standard biochemical and cell biological experiments.

Lab Personnel

Rana Al-Hallaq, Ph.D. (Send e-mail)
Kai Chang, M.D. (Send e-mail)
Lisa Dunbar, Ph.D. (Send e-mail)
M'hamed Grati, Ph.D. (Send e-mail)
Martin Horak, Ph.D. (Send e-mail)
Ronald S. Petralia, Ph.D. (Send e-mail)
Kate Prybylowski, Ph.D. (Send e-mail)
Gail Seabold, Ph.D. (Send e-mail)
Catherine Craft Swanwick, Ph.D. (Send e-mail)
Ya-Xian Wang, M.D. (Send e-mail)
Zhaohong Yi, Ph.D. (Send e-mail)

Selected Publications

• Sans N, Wang PY, Du Q, Petralia RS, Wang YX, Nakka S, Blumer JB, Macara IG, Wenthold RJ. mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression. Nature Cell Biololgy 7(12):1079–1090, 2005.
• Prybylowski K, Chang K, Sans N, Kan L, Vicini S, Wenthold RJ. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron 47(6):845–57, 2005.
• Hawkins LM, Prybylowski K, Chang K, Moussan C, Stephenson FA, Wenthold RJ. Export from the endoplasmic reticulum of assembled N-methyl-d-aspartic acid receptors is controlled by a motif in the c terminus of the NR2 subunit. The Journal of Biological Chemistry 279(28):28903–10, 2004.
• Sans N, Vissel B, Petralia RS, Wang YX, Chang K, Royle GA, Wang CY, O'Gorman S, Heinemann SF, Wenthold RJ. Aberrant formation of glutamate receptor complexes in hippocampal neurons of mice lacking the GluR2 AMPA receptor subunit. Journal of Neuroscience 23:9367–9373, 2003.
• Sans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C, Vicini S, Wenthold RJ. NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex. Nature Cell Biology 5(6):520–530, 2003.
• Wenthold RJ, Prybylowski K, Standley S, Sans N, Petralia RS. Trafficking of NMDA receptors. Annual Reviews of Pharmacology and Toxicology 43:335–358, 2003.
• Prybylowski K, Fu Z, Losi G, Hawkins LM, Luo JH, Chang K, Wenthold RJ, Vicini S. Relationship between availability of NMDA receptor subunits and their expression at the synapse. Journal of Neuroscience 22(20):8902–8910, 2002.
• Roche KW, Standley S, McCallum J, Ly CD, Ehlers MD, Wenthold RJ. Molecular determinants of NMDA receptor internalization. Nature Neuroscience 4:794–802, 2001.
• Sans N, Petralia RS, Racca C, Wang Y-X, McCallum J, Wenthold RJ. Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway. Journal of Neuroscience 21:7506–7516, 2001.
• Sans N, Petralia RS, Wang Y-X, Blahos J II, Hell JW, Wenthold RJ. A developmental change in NMDA receptor-associated proteins at hippocampal synapses. Journal of Neuroscience 20:1260–1271, 2000.
• Standley S, Roche KW, McCallum J, Sans N, Wenthold RJ. PDZ-domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28:887–898, 2000.
• Petralia RS, Esteban JA, Wang Y-X, Partridge JG, Zhao H-M, Wenthold RJ, Malinow R. Selective acquisition of AMPA receptors during postnatal development suggests a molecular basis for silent synapse. Nature Neuroscience 2:31–36, 1999.

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