Alternative splicing of latrophilin-3 controls synapse formation. (https://www.nature.com/articles/s41586-023-06913-9)

These scientists wanted to understand how connections between brain cells, called synapses, are formed. They focused on a protein called Latrophilin-3, which helps in the formation of synapses in a part of the brain called the hippocampus.

To figure out how Latrophilin-3 works, the scientists did experiments on mice. They discovered that Latrophilin-3 organizes synapses through two different pathways. The first pathway involves a process called Galpha(s) signaling, where Latrophilin-3 sends signals to other parts of the cell. The second pathway involves the recruitment of special protein structures that help in synapse formation.

The scientists also found that the way Latrophilin-3 works depends on how it is made. There are different versions of Latrophilin-3, which are made through a process called alternative splicing. These different versions can either use the Galpha(s) signaling pathway or a different pathway called Galpha(12/13) signaling.

To test the importance of the Galpha(s) pathway, the scientists used a technique called CRISPR to change the way Latrophilin-3 is made in the mice. They found that when the Galpha(s) pathway was blocked, the mice had problems with their synapses, similar to when Latrophilin-3 was completely removed.

Interestingly, they also discovered that the Galpha(s) pathway versions of Latrophilin-3 can recruit special protein structures called condensates. These condensates help in clustering the proteins needed for synapse formation. This clustering is important for synapse formation to happen properly.

The scientists also found that the activity of the brain cells can influence which version of Latrophilin-3 is made. When the brain cells are active, it promotes the production of the Latrophilin-3 version that uses the Galpha(s) pathway.

In conclusion, this study showed that the way Latrophilin-3 works in the brain is through two different pathways: Galpha(s) signaling and the recruitment of protein condensates. The specific version of Latrophilin-3 made by the brain cells determines which pathway is used. This discovery helps us understand how synapses are formed in the brain and how brain activity can influence this process.

Wang S., DeLeon C., Sun W., Quake SR., Roth BL., Sudhof TC. Alternative splicing of latrophilin-3 controls synapse formation. Nature. 2024 Feb;626(7997):128-135. doi: 10.1038/s41586-023-06913-9. Epub 2024 Jan 17.