Adhesive substance at nerve synapses is importantin memory and learning, research shows

PASADENA—A sticky molecule found at the junctions of brain cells may be a crucial chemical ingredient in learning and memory, neuroscientists have discovered.

In the current issue of the journal Neuron, Erin Schuman and her students at the California Institute of Technology report that a calcium-dependent family of molecules known as cadherins plays a significant role in chemically joining the synapses (the junctions of nerves). Neuroscientists believe that the environment of the synapses is where memories are stored.

"These cadherins may form a sort of zipper-like structure at the junction of the presynaptic cell and the postsynaptic cell," says Schuman, who is a Howard Hughes Medical Institute investigator and assistant professor of biology at Caltech

"We show in this study that these molecules participate in making the synapses bigger and stronger, a process called 'long-term potentiation' that may be involved in memory storage."

According to Schuman's graduate student Lixin Tang, who is coauthor of the paper, the new research involves turning off the cadherins to see what happens to long-term potentiation when the synapses have to do without them.

"It has been known for some time that cadherins are important during early development," says Tang. "But they are also expressed well into adulthood. So we were interested in seeing what would happen when cadherin was disrupted in the adult brain."

The researchers shut off the cadherins in the hippocampuses of adult mice and rats with various antibodies targeting various adhesion sites, as well as with inhibitory peptides. The results showed that long-term potentiation was significantly reduced when the cadherins were temporarily inactivated at synapse junctions.

However, the overall signal transmission of the synapses and their structural integrity were unchanged by the antibodies. This would indicate that the cadherins are used very specifically by the nerves for changing the strength of synapses, but not for the basic transmission of nerve impulses.

Finally, the inhibitory peptides were indeed effective in shutting down long-term potentiation, but only if they were introduced at the beginning of long-term potentiation. When the peptides were introduced about 30 minutes afterward, they had no effect.

This suggests that there may be factors other than the cadherins involved in long-term potentiation, and that these factors cannot be blocked by the peptides, Schuman explains. Like the antibodies, the peptides have no effect on baseline signal transmission or structural integrity when they disrupt the cadherins.

Also, it is known that calcium transiently leaves the synaptic junction during nerve impulses. And further, cadherins require calcium in order to stick together. Therefore, a possibility to explain the selective effect of the peptides on long-term potentiation initiation is that calcium leaving the junction during synaptic activity transiently destabilizes the cadherin bonds, thus allowing the blocking action of the peptides.

Schuman and colleagues find that elevating the concentration of calcium in the extracellular solution protects the cadherins from the inhibitory peptides. This suggests that cadherins might be able to work as "activity sensors" outside nerve cells by monitoring changes in calcium and then changing their binding to one another.

Taken together, the new results suggest that the cadherins are important in changing synapses in ways thought to be important to learning and memory. In addition to Schuman and Tang, the authors of the paper also include Chou P. Hung, who graduated from Caltech in 1996.

The research was supported by the Howard Hughes Medical Institute.