Scientists reveal how astrocytes help neurons form successful connections

October 12, 2017
Scientists reveal how astrocytes help neurons form successful connections
Fluorescently labeled astrocytes (large green structures) and neuronal postsynaptic receptors (red). Credit: Salk Institute

To have a good phone conversation, you need a good cellular connection. What's true for mobile phones also turns out to be true for neurons.

Salk Institute scientists have discovered that brain cells called astrocytes initiate communication between pairs of early in development by inducing specific changes in both members of the pair. The work, published in Neuron on October 11, 2017, has important implications for neurodevelopmental disorders such as autism, ADHD and schizophrenia that are thought to result at least partly from faulty communication between neurons.

"When the brain is forming, all the neurons have to make the right connections with each other to function properly," says Nicola Allen, an assistant professor in Salk's Molecular Neurobiology Laboratory and senior author of the paper. "But how that happens, and what the molecular signals are in the process, is still something we don't fully understand."

Although neurons are the most well known cells in the brain, they make up just half the total number of cells. The other half includes various types of cells, the most abundant of which are astrocytes. In recent years, scientists have learned that astrocytes are necessary for neurons to form active connections with each other across tiny gaps called synapses. But the exact mechanism behind the process has been a mystery—until now.

Over the years, various labs identified different proteins that astrocytes secrete which seem to influence neuronal development. But none of the proteins they discovered resulted in functional synapses that promote active communication between neurons. The synapses were essentially silent.

Then, as a postdoctoral researcher, Allen discovered that a protein secreted by astrocytes called glypican 4 somehow induced communication between nearby neurons. With glypican 4 present, neurons sending information (termed "presynaptic") were partnering effectively with neurons receiving it ("postsynaptic"). The neurons exchange messages in the form of chemicals that travel across the gap, and are received by molecular docking stations on the receiving end, known as "receptors." What Allen didn't know was how. Once she established her own lab at Salk, she set out to uncover the details.

Credit: Salk Institute

Isabella Farhy-Tselnicker, a Salk research associate and the paper's first author, adds, "Following up on Nicola's work on glypican 4, I wanted to figure out what happens in the neurons and the synapse to make the synaptic connection. What are the processes? Who are the cells talking to?"

Allen and Farhy-Tselnicker began by treating cultures of neurons with either glypican 4 or another -secreted protein called thrombospondin, which induces changes in neurons but doesn't result in any synaptic communication. The idea was to compare the two sets of cultures and see what was different in the ones treated with glypican 4 that made those neurons able to communicate.

The duo found that 49 genes were activated in response to treatment with glypican 4, but only 3 were activated in response to thrombospondin. The fact that there was no overlap between the genes suggested that the two proteins are involved in very different cellular systems, and that glypican 4 is critical to making synapses active.

Further experiments revealed that glypican 4 increases the numbers of specific kinds of receptors on the receiving neurons (postsynaptic). Glypican 4 recruits the receptors to the cell surface by inducing the release of a protein called neuronal pentraxin 1 (NP1) that directly binds to the receptors. Without NP1 binding to the receptors, Allen and Farhy-Tselnicker found, remained silent. Thus, glypican 4 is needed to make postsynaptic neurons receptive to input, the researchers say.

Other studies have found that NP1 is released by the neurons sending information. So the Salk team also looked into what might be happening on the presynaptic side of the connection. They found that the presynaptic neurons released NP1 specifically in response to glypican 4, meaning that a single protein released by astrocytes is responsible for enabling meaningful connections by acting on both sending and receiving neurons.

"We did not expect to find that a secreted by astrocytes would impact neurons on both sides of the synapse," adds Allen, who holds the Hearst Foundation Development Chair. "Not only does this reveal a more complex role for astrocytes as organizers of active synaptic connections, it also offers an exciting therapeutic target for synaptic dysfunction.

The lab's future work will explore ways of targeting astrocytes to come up with novel therapies for neurological disorders.

Explore further: Change in the brain: Astrocytes finally getting the recognition they deserve

More information: Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation. Neuron. DOI: dx.doi.org/10.1016/j.neuron.2017.09.053

Related Stories

Change in the brain: Astrocytes finally getting the recognition they deserve

April 25, 2016
Researchers at the RIKEN Brain Science Institute (BSI) in Japan have demonstrated that astrocytes help control the strength of connections between neurons. Published in Proceedings of the National Academy of Sciences, the ...

Scientists find interaction between two key proteins regulates development of neurons

September 14, 2017
Salk Institute scientists have discovered that an interaction between two key proteins helps regulate and maintain the cells that produce neurons. The work, published in Cell Stem Cell on September 14, 2017, offers insight ...

Key synapse formation regulator identified

August 22, 2017
Professor Ko Jae-won at Korea Advanced Institute of Science and Technology (KAIST) has conducted a study of the three-dimensional structure of proteins that regulate neuronal cell connections for the first time, and has identified ...

Researchers upend longstanding idea that astrocytes can't be differentiated from each other

July 14, 2017
From afar, the billions of stars in our galaxy look indistinguishable, just as the billions of star-shaped astrocytes in our brains appear the same as each other. But UCLA researchers have now revealed that astrocytes, a ...

Study implicates glial cells in fragile X syndrome

October 4, 2016
Research on fragile X syndrome, the most common inherited cause of mental retardation, has focused mostly on how the genetic defect alters the functioning of neurons in the brain. A new study focusing on a different type ...

Recommended for you

Our memory shifts into high gear when we think about raising our children, new study shows

December 15, 2017
Human memory has evolved so people better recall events encountered while they are thinking about raising their offspring, according to a new study conducted by researchers at Binghamton University, State University of New ...

Offbeat brain rhythms during sleep make older adults forget

December 15, 2017
Like swinging a tennis racket during a ball toss to serve an ace, slow and speedy brainwaves during deep sleep must sync up at exactly the right moment to hit the save button on new memories, according to new UC Berkeley ...

Study finds graspable objects grab attention more than images of objects do

December 15, 2017
Does having the potential to act upon an object have a unique influence on behavior and brain responses to the object? That is the question Jacqueline Snow, assistant professor of psychology at the University of Nevada, Reno, ...

Little understood cell helps mice see color

December 14, 2017
Researchers at the University of Colorado Anschutz Medical Campus have discovered that color vision in mice is far more complex than originally thought, opening the door to experiments that could potentially lead to new treatments ...

Scientists chart how brain signals connect to neurons

December 14, 2017
Scientists at Johns Hopkins have used supercomputers to create an atomic scale map that tracks how the signaling chemical glutamate binds to a neuron in the brain. The findings, say the scientists, shed light on the dynamic ...

Activating MSc glutamatergic neurons found to cause mice to eat less

December 13, 2017
(Medical Xpress)—A trio of researchers working at the State University of New York has found that artificially stimulating neurons that exist in the medial septal complex in mouse brains caused test mice to eat less. In ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.