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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.

In late 2014, led by Cagla Eroglu PhD, assistant professor of cell biology and neurobiology at Duke University School of Medicine, researchers identified that a protein called 'hevin', helps new neurons connect from the thalamus to the cortex in mice. Hevin is produced by crucial non-neuronal brain cells called astrocytes.

"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.

"There is an interesting code between neurexins and neuroligins that determines whether they form contacts between each other. Some forms of these molecules seem to prefer each other and make contacts, while some don't interact with each other at all.

"What we found — which was surprising — is that astrocytes secrete hevin to alter this code."

Carla Eroglu PhD, Assistant Professor, Cell Biology and Neurobiology, Duke University School of Medicine.

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.

Through collaboration with Alexandre Medina's lab at the University of Maryland, Eroglu's team identified that mice missing hevin were unable to strengthen thalamus-cortex connections in response to visual experience as young mice.

However, supplying hevin to the astrocytes of these mice overcame the problem.

"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.

Abstract Highlights
•Astrocyte-secreted hevin is a pre- and postsynaptic organizer
•Hevin induces thalamocortical synapse formation by bridging NRX1α and NL1
•Hevin is required for recruitment of NL1 and NMDAR to excitatory synapses in vivo
•Astrocyte-secreted hevin is necessary for ocular dominance plasticity

Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.

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.

Cell, Jan. 14, 2016. DOI: 10.1016/j.cell.2015.11.034
CITATION: "Astrocytes Assemble Thalamocortical Synapses by Bridging

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Jan 28, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Neurexins are present on the message-sending side of neurons — whereas neuroligins
are on the receiving end. Astrocytes promote the formation of synapses
by modulating neurexin/neuroligin adhesion by secreting hevin.

Image Credit: Cagla Eroglu PhD




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