A New Understanding of Synapses

In 1959, Edward Gray showed that the minuscule gaps between neurons where chemical messages are sent, called synapses, come in two main varieties, which researchers later dubbed “excitatory” and “inhibitory.”

Inhibitory synapses act as the brakes in the brain, preventing it from becoming overexcited. Researchers thought they were less sophisticated than their excitatory counterparts because relatively few proteins were known to exist at these structures. But a new study by Duke University scientists, published in Science, overturns that assumption, uncovering 140 proteins that have never been mapped to inhibitory synapses.

“It’s like these proteins were locked away in a safe for over 50 years, and we believe that our study has cracked open the safe,” said the study’s senior investigator Scott Soderling, an associate professor of cell biology and neurobiology at Duke. “And there’s a lot of gems.”

In particular, 27 of these proteins have already been implicated by genome-wide association studies as having a role in autism, intellectual disability and epilepsy, Soderling said, suggesting that their mechanisms at the synapse could provide new avenues to the understanding and treatment of these disorders.

“The inhibitory synapse is just as important as the excitatory synapse, but we didn’t have a good way of purifying the proteins that were there, so we didn’t understand how it worked,” Soderling said.

In the new study, postdoctoral researcher Akiyoshi Uezu in Soderling’s group used a relatively recent labeling technique called BioID, which uses a bacterial enzyme to fish for any nearby proteins and bind to them irreversibly inside a living mouse. The captured proteins are then recovered from the tissue and identified using established methods for characterizing proteins.

The afternoon Soderling and Uezu realized the technique was pulling new proteins from the inhibitory synapse “we both almost fell out of our chairs,” Soderling said. “We saw this huge list of these really exciting proteins that no one had ever seen before.”

The team plans to explore the role of inhibitory synapses in the formation of long-term memory, which is enabled by synapses changing the strength of their connections over time. How inhibitory connections operate in memory is much less understood than in excitatory synapses, Soderling said.