"The question is: how can you form synapses with the right partners?" says Huang, "and what mechanism is involved to achieve the necessary specificity?" Some have proposed that nerve cells secrete some kind of repulsive or attractive molecules. "But when you are in the cortex, the distance between different potential partners is so minuteit's inconceivable that kind of mechanism could work."
"It's more plausible that the cortical neuron's strategy is to initiate synapse formation with almost any nearby target and then to test it, by trying to communicate using synaptic transmission," Huang explains. "Most of these tentative connections don't prove to be correct and will be eliminated. Only those between functionally compatible neurons will be validated and strengthened."
Building upon the knowledge that cellular "glues," in the form of cell-adhesion molecules called neurexins and neuroligins, are needed to make a preliminary connection, Huang and Fu observed in live cortical circuits precisely how they interacted. "They work like a zipper: two neuronscalled pre-synaptic and post-synapticare touching; there are adhesion molecules coming from both sides, and they actually lock," Huang says.
Their key finding concerns the steps that occur following this preliminary zippering: the presynaptic neuron sends a quantity of neurotransmitter across to the prospective partner. But how does this neurotransmission get translated into molecular adhesion? Huang and Fu looked closely at neurexins, proteins that interact with neuroligins to form the zipper that holds synapses together. They found for the first time that two forms of neurexin, called alpha and beta, have very different properties, and respond in different ways to neural activity.
"The alpha neurexin molecule seems to be acting like a search engine," says Huang. Widely distributed along
|Contact: Peter Tarr|
Cold Spring Harbor Laboratory