Scientists Pinpoint Molecules That Generate Synapses

Scientists from Harvard University and Washington University in St. Louis describe the findings in the July 23 issue of the journal Cell.

"This is very basic work, far from any clinical applications at this point," says author Joshua R. Sanes, professor of molecular and cellular biology in Harvard's Faculty of Arts and Sciences. "Still, one can think of lots of cases, from normal aging to mental retardation to neurodegenerative disease, where making more synapses or preventing synapse loss might be beneficial. This finding may eventually point the way to new therapies."

The work, using mice as a model, was conducted while Sanes and co-author Hisashi Umemori were at Washington University.

Synapses are the sites where neurons communicate with each other to form the large and complex information-processing networks of the brain. These networks are highly modifiable because the synapses between neurons are plastic, leading to changes that underlie learning. Synapses are also the targets of nearly all psychoactive drugs, including both prescription medications and illicit drugs.

"We knew that the apparatus for sending and receiving chemical and electrical signals was concentrated at the synapses where neurons connect with each other," Sanes says. "We wanted to determine how these special sites form."

As the early nervous system develops into a dense tangle of neurons, synapses sprout at places where neurons grow close to one another. In order for a synapse to actually form, Sanes and Umemori believed, certain key molecules would have to flow across the gap between two neurons to commence development of a synapse linking them.

Umemori spent several years scanning neurons in culture for these pioneering molecules that set in motion the linking of neural networks. In the end he fingered a molecule called FGF22, along with several of its close relatives, as key to setting in motion the construction of synapses. Umemori confirmed FGF22's role by showing that mice in which FGF22 was inactivated failed to grow synapses; conversely, when added to neurons in culture, the molecule stimulates synapse formation.

Sanes and Umemori determined that FGF22 works to build synapses in the brain's cerebellum, a critical center for motor control; it's unclear whether it also serves as a signal to foster synapse growth between neurons in other areas. Two other members of the FGF family, FGF7 and FGF10, are very similar in structure, and may play similar roles in other areas of the nervous system.

Sanes and Umemori's co-authors on the Cell paper are Michael W. Linhoff and David M. Ornitz, both at Washington University Medical School. The work was supported by the National Institutes of Health.