CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
|3 Autism-linked molecules wire up neurons
New research from Duke University reveals how three proteins work together to wire up a specific area of the brain responsible for processing sensory input.
Published in the Jan. 14 issue of the journal Cell, the research may give insight into how brain disorders such as autism, depression and addiction occur. The research focused on neurons that pass information from the brain's thalamus — which processes sensory information — to the cortex — important for memory, attention and consciousness.
"We may have pinpointed a developmental process ... critically impaired in diseases such as autism, and that's really exciting," added Eroglu.
The group had thought that two other types of proteins, neurexins and neuroligins, could be involved. Neurexins are present on the message-sending side of neurons — whereas neuroligins are on the receiving end. It's believed these proteins align new neuronal contacts in order for signals to pass between the small synapse spaces.
In particular, Eroglu's team found that hevin causes two specific members of these protein families — 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 then revealed specific areas on the hevin protein that latch onto both neurexin-1 alpha and neuroligin-1B, to form a molecular bridge across synapses. They then located the area 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. But 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 types of synapses to form.
"This result nicely illustrated that hevin secreted by astrocytes is particularly necessary for ushering the formation of synapses," adds Sandeep Singh, postdoctoral researcher in Eroglu's lab.
The group plans to continue study of genetic mutations linked to autism that may affect hevin's ability to bridge neurexin and neuroligin.
Other authors on the study are Nisha Pulimood, Alex Manhaes, Wandilson Rodrigues-Junior of the University of Maryland; Hayley Dingsdale, Yong Ho Kim, Louis-Jan Pilaz, Il Hwan Kim, Arin Pamukcu, Eray Enustun, Zeynep Ertuz, Scott Soderling, Debra Silver and Ru-Rong Ji of Duke; and Peter Scheiffele of the University of Basel in Switzerland.
The study was supported by the National Institutes of Health (DA031833, DE22743, and DE17794, NS083897, NS092419), Brumley Neonatal Perinatal Research Institute, Swiss National Science Foundation, Ruth K. Broad Biomedical Research Foundation, Howard Hughes Medical Institute, Holland-Trice Brain Research Scholar Award, Esther A. and Joseph Klingenstein Fund, and Alfred P. Sloan Foundation.
Laboratory members: Nrx1-alpha and NL1 via Hevin," Sandeep K. Singh, Jeff A. Stogsdill, Nisha S. Pulimood, Hayley Dingsdale,Yong Ho Kim, Louis-Jan Pilaz, Il Hwan Kim, Alex C. Manhaes, Wandilson S. Rodrigues-Junior, Arin Pamukcu, Eray Enustun, Zeynep Ertuz, Peter Scheiffele, Scott Soderling, Debra L. Silver, Ru-Rong Ji, Alexandre E. Medina and Cagla Eroglu.