Researchers have found that the neurodevelopmental disorder Costello syndrome may be due to deregulated signaling to neurons by a supporting cell type, the astrocyte. The findings suggest that modulating the communication between astrocytes and neurons could be an approach to treating the disorder.
The work, senior author Erik Ullian of the University of California at San Francisco, told BioWorld Today, "really illustrates that astrocytes in disease can have profound brainwide effects on development and function."
Costello syndrome is relatively rare, but is part of a much larger family of neurodevelopmental disorders, the RASopathies, in which the RAS gene itself or other members of the RAS/Map kinase pathway are mutated.
Collectively, Ullian said, the RASopathies are "one of the most common, if not the most common, neurodevelopmental disorder."
To most biopharma folk, RAS is better known as an oncogene than a neuropsychiatric one. And individuals with RASopathies do have a high risk of cancer. Individuals with Costello syndrome, in which HRAS is mutated, have a 15 percent lifetime chance of developing malignant tumors – the highest risk of any of the RASopathies.
But RASopathies typically also lead to cognitive disabilities as well as other medical issues. In Costello syndrome, those issues most often include failure to thrive as a result of feeding difficulties in infancy, heart defects, and skin and bone abnormalities.
The cognitive disabilities in Costello syndrome result from structural abnormalities in the brain. Previous research had focused on changes that increased HRAS signaling brings about in the neurons themselves.
In their experiments, which they published in the May 6, 2015, issue of Science Translational Medicine, Ullian and his colleagues looked at what increased HRAS signaling did to astrocytes.
Once regarded as more or less passive structural support for neurons, which they outnumber in the brain, astrocytes are now recognized as playing multiple roles, including propagating information over long distances and communicating with interneurons.
Ullian and his colleagues used two different model systems, astrocytes from induced pluripotent stem cells (iPSCs) from Costello syndrome patients, and transgenic mice bearing an HRAS mutation.
They found that astrocytes with an HRAS mutation "become remarkably large and complex," a striking feature for cells that are naturally already large and complex.
And, he added, "They completely change the environment in which the neurons reside. . . . In a sense, they are maturing the brain too rapidly."
In their work, Ullian and his colleagues found that the Costello-like astrocytes generated more proteins that are important in the extracellular matrix, such as proteoglycans and extracellular matrix remodeling factors. As a result, they formed so-called perineuronal nets, which are meant to stabilize neuronal circuits, too early, before those circuits had actually had a chance to form.
During development, neurons are primed to wire themselves up during so-called critical periods, when they are extremely sensitive to incoming activity and strengthen connections where they receive such input.
In Costello syndrome, it appears that the astrocytes are on a faster developmental schedule than the neurons. That means critical periods are occurring, and ending, prematurely when the neurons are not yet ready for them. And as a result, neurons do not wire themselves up correctly.
Ullian contended that the effects on astrocytes may contribute just as much or even more to clinical symptoms. He noted that at this point, that idea lacks firm experimental support. But their results seem to indicate that astrocytes may be more vulnerable because "although neurons certainly are affected in the disease . . . they also seem to have lots of ways of regulating the pathway," and so they are able to compensate for its increased signaling to a degree.
Astrocytes, on the other hand, "don't seem to have those regulatory mechanisms."
The work also suggests that there is what he termed "an astrocyte-interneuron axis" that he said may be affected in many neurodevelopmental disorders, not just Costello syndrome or even just the RASopathies.
Costello syndrome has some similarities to autism spectrum disorders, and it is possible that treatments that allow interneurons to wire themselves up correctly by slowing down astrocyte maturation could be useful in other autism spectrum disorders as well.
Recent work has shown that faulty wiring may be actively maintained, and so neurodevelopmental disorders – which were once thought to be beyond the reach of treatment once critical periods had passed – may in fact be amenable to therapeutic intervention even after circuits have formed. (See BioWorld Today, April 12, 2012, and March 4, 2013.)
Ullian said that in principle, the same might be true for Costello syndrome. Whether early treatment is required to have an effect, or drugs – either RAS/Map kinase inhibitors on inhibitors of transcription factors that are downstream of the RAS/Map kinase pathway – "is something we are pursuing now," he said.