The normal functioning of the brain depends upon the ability of nerve cells to rapidly transmit chemical signals to each other. This chemical transmission is accomplished through cell contacts called synapses. Synapses form mainly during embryonic and fetal life, and childhood, though they may form in adult life as well. One nerve cell may make as many as 50,000 synapses, and as there are over a billion nerve cells in the brain there would be over a trillion synapses in the brain. The synapse is a relatively stable contact, tightly binding together the nerve cells involved. This tight contact provides both the stability and closeness necessary for chemical signals to be predictably and rapidly transferred between neurons. Recent research has provided considerable insight into the mechanisms involved in chemical neurotransmission. However, very little is known about the molecules involved in generating the adhesiveness or mechanical stability in the zone of synaptic contact. About a half-dozen proteins have been identified recently which reside almost exclusively in the cell membranes in the zone of synaptic contact in developing and adult brains of mammals (and probably other vertebrates as well). Based upon their preliminary characterization these proteins appear to be good candidates to be at least some of the molecules involved in synaptic adhesion. This proposal outlines experiments which would investigate further the ability of these proteins to function as adhesion molecules. A number of approaches will be taken. These molecules will be isolated from synaptic junctions of rats and examined for their ability to bind each other or to other synaptic molecules. For example, the proteins will be linked to tiny beads alone or in different combinations to see if they can promote the aggregation of the beads (as has been seen for other kinds of adhesion molecules). In a second approach, the isolated proteins will be coated on the surface of tissue cult ure dishes or inert beads to see if they have any ability to act as a favorable substrate for the formation of synaptic contacts by cultured nerve cells. In a third approach, rabbit antibodies will be generated to these proteins to see if they can either disrupt the stability of the synaptic contact or prevent synapses from forming. If one or more of these proteins appears to have the properties of an adhesion molecule then a new grant proposal will be developed to further study their molecular organization and the regulation of their synthesis and turnover.
