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Deconvolved Image of acetylcholine receptors in micro-aggregates within a larger cluster.

 

Herman Gordon

Associate Professor of Cell Biology & Anatomy
and Molecular & Cellular Biology
Member, Committee on Neuroscience

B.A., Harvard College
Ph.D., California Institute of Technology
Postdoc, University of California, San Francisco

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Molecular Mechanisms of Synaptogenesis

At the heart of how we are able to think lies a problem in the organization of molecules on cell membranes. It is now generally accepted that the ability of our nervous systems to learn and change reflects an underlying ability of cells of the nervous system to dynamically alter the strengths of their connections. These connections, called synapses, are cell surface specializations containing functional and structural molecules at very high local concentrations. One very important way by which synaptic strength can be modulated is by changing the size of the synapses. In general, bigger synapses are stronger synapses.

Synapses become bigger by recruiting more constituent molecules. Although, many of these molecules have now been identified at the model synapse of choice, the neuromuscular junction, how they aggregate and disperse at a synaptic connection remains largely mysterious. My colleagues and I are taking a two-pronged approach to the problem. First, we are using a muscle cell culture model in which we can observe the aggregation of known synaptic molecules in response to neurons or active factors such as neural agrin. There appear to be 2 basic pathways which regulate the aggregation of synaptic molecules: one involves signal transduction and tyrosine phosphorylation while the other may involve structural interactions on the extracellular surface. When observed in detail, the aggregation is quite dynamic in surprising ways that we hope will promote a better understanding of the underlying processes.

In a second approach, we have taken to modeling what we know about the molecular players and exploring whether these properties in conjunction with a minimum of assumptions can indeed produce aggregates that behave similarly to those seen in living cells. There are two classes of mechanism by which molecules can aggregate on the cell surface: rafting and co-anchoring. In the former, an energy of association characterizes lateral interactions between synaptic molecules while in the latter, the immobilization of one or more molecules can be propagated to neighbors. Each class of mechanism has its advantages and disadvantages in terms of creating large dynamic structures. What we see in synapses may be a blend of both mechanisms. The challenge now is to formulate testable hypotheses and to use the modeling to focus our attentions on the most important molecular details.

In the future, I hope to transfer what we learn from this interdisciplinary effort to attack the larger question of how it is that synapses can compete with each other. How does one synapse get larger at the expense of another? In the end, I hope that we will someday collectively understand the functioning of the mind at all levels from behavior to network properties to molecular interactions.

Selected Publications:

Graf, R.A., Kater, S.B., and Gordon, H. (1999) Muscle contact-induced calcium signaling in growth cones and neurites. Dev. Neurosci., 21(6): 409-416.

Grow, W.A., Ferns, M., and Gordon, H. (1999) Agrin-independent activation of the agrin signal transduction pathway. J. Neurobiol., 40: 356-365.

Grow, W.A., Ferns, M., and Gordon, H. (1999) A Mechanism for acetylcholine receptor clustering distinct from agrin signaling. Dev. Neurosci., 21(6): 436-443.

Grow, W.A. and Gordon, H. (2000) AChRs are required for postsynaptic scaffold assembly driven by the agrin signaling pathway. Eur. J. Neurosci., 12: 467-472.

Grow, W.A., and Gordon, H. (2000) Sialic Acid inhibits agrin signaling in C2 myotubes. Cell & Tissue Res., 293: 273-279.

St. John, P., and Gordon, H. (2001) Agonists Cause Endocytosis of Nicotinic Acetylcholine Receptors on Cultured Myotubes. J. Neurobiol., 49: 212-223.

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