Trio of autism-linked molecules orchestrate neuron connections

Trio of autism-linked molecules orchestrate neuron connections
The new work focused on the neurons that pass information from the brain's thalamus -- which processes sensory information -- to the cortex, which is important for memory, attention and consciousness, among other roles. Previously researchers found that a protein called 'hevin', produced by crucial non-neuronal brain cells called astrocytes, helps new neuronal connections form from the thalamus to the cortex in mice, but exactly how was unclear.

The group thought that two other types of proteins, neurexins and neuroligins, might be involved. Neurexins are present on the message-sending sides of neurons, whereas neuroligins are on the receiving ends. These proteins are thought to align new neuronal contacts so that they can pass signals within the small gaps between them, called synapses.

The team found that hevin causes two specific members of these protein families which would not normally interact -- neurexin-1 alpha from thalamus neurons and neuroligin-1B from the cortex -- to wire neurons of the thalamus to those of the cortex.

A battery of biochemical experiments showed specific places on the hevin protein that latched onto both neurexin-1 alpha and neuroligin-1B, forming a molecular bridge across the synapses. They also created different versions of hevin in which various regions were missing, finding the necessary place on the hevin molecule that made the link between neurexin 1 alpha and neuroligin 1B.

Mice lacking either neurexin-1 alpha or neuroligin-1 have problems forming thalamus-cortex connections. In these mice, synapses by neighboring neurons in the cortex take over. Mice lacking hevin have similar issues.

"Perhaps one reason our brains have so many different forms of neurexins and neuroligins is that they encourage specific neurons to find one another during development and make certain kinds of connections," author said.

Before this study, neither neurexin 1 alpha nor neuroligin 1 were recognized as important in thalamus-cortex wiring. Astrocytes were not known to help guide these kinds of synapses to form.

The new findings also illustrate the importance of hevin in developing neuronal connections shaped by the sensory information an animal takes in.

The team also found that mice missing hevin were unable to strengthen thalamus-cortex connections in response to changes in visual experience in young mice. Supplying hevin to the astrocytes of these mice fixed this problem.