Vascular development may be at risk in autism

July 13, 2020

A Canadian collaboration led by Dr. Baptiste Lacoste has undertaken the first ever in-depth study of vasculature in the autistic brain. The product of four years of work, a paper published today in Nature Neuroscience lays out several lines of novel evidence that strongly implicate defects in endothelial cells--the lining of blood vessels--in autism.

Dr. Lacoste, a scientist at The Ottawa Hospital and an assistant professor in the University of Ottawa's Faculty of Medicine and Brain and Mind Research institute, heads a lab that specializes in neurovascular interactions in health and disease. In collaboration with researchers at McGill University, Laval University, and the National Research Council of Canada, Dr. Lacoste's team used a mouse model with one of the most common genetic mutations found in autism spectrum disorder--16p11.2 deletion, or "16p" for short.

The team, in which Dr. Lacoste's graduate student Julie Ouellette and research associate Dr. Xavier Toussay played prominent roles, also used cells derived from the tissue of human autistic adults who carry the 16p mutation.

Nerves and blood vessels not in synch

"If you imagine you have a luxury car--a Ferrari--and it's beautiful, sitting in your garage. But if you don't put gas in the tank, the car won't drive," says Dr. Lacoste. "It's exactly the same with the brain. It's the most complex organ, but if you don't have blood supply, the brain just doesn't work properly."

Normally, when brain cells light up, blood rushes to the active brain region, a phenomenon called 'neurovascular coupling'. But when neurons of mice with the 16p deletion are stimulated, this study found that vascular responses in those brain regions were delayed and weaker.

This disconnect--or 'neurovascular uncoupling'--was shown to originate in the blood vessels themselves: Arteries isolated from these mice and kept alive in a medium also showed a weak and sluggish response to chemicals that induce dilation of blood vessels. The team further isolated the source of the deficit in the endothelium, as opposed to the other cell types, such as muscle cells, that surround blood vessels.

Difficulties in development

Dr. Lacoste's work further shows that problems with blood vessels begin very early in life for those who carry the 16p deletion. In a petri dish, both human-derived and mouse endothelial cells with the mutation were unable to sprout the extensions that normally connect blood vessels to each other, allowing the vascular network to expand and grow. Endothelial cells in the brains of newborn autistic mice had the same problem.

By adolescence, the mice still showed reduced vascular density in their brains. Interestingly, in contrast to the problems in the circulatory system, the researchers found that the neurons in the brains of these young mice appeared to be surprisingly well organized.

As the mice grew, other cells in the brain compensated for their dysfunctional endothelial cells, so that by adulthood they had developed a full network of blood vessels. However, as the researchers' previous experiments showed, these blood vessels remained dysfunctional in adult mice.

"It's a bit like if a plumber comes to your house and does a bad job installing the pipes," says Dr. Lacoste. "You will have trouble getting the right water pressure in your sink from then on."

Blood vessels and autistic behavior

When a person or mouse carries a 16p mutation, that genetic difference is replicated in every cell in their body. This makes it harder to pin down the cause of systemic developmental differences.

To address this difficulty, Dr. Lacoste's team generated mice that only expressed the mutation in their endothelial cells--so-called "conditional mutants". These mice showed similar deficits in their vascular development as whole-body mutants.

Remarkably, although every other cell in their brain and body was genetically normal, these conditional mutants displayed some behavioural signs of autism: hyperactivity, stereotypic movements, and motor learning impairment.

This indicated that the problems in the blood vessels contributed to neuronal dysfunction, which in turn led to the outward signs and symptoms of autism.

Further avenues of inquiry

The researchers used an equal number of male and female mice and found more pronounced effects in male mice, suggesting that females may have other tools, such as estrogen, that either compensate or mask the deficits. They suggest this as an avenue of inquiry, as well as the role of blood vessels in a broader range of neurodevelopmental disorders, which could lead to novel diagnostics and therapeutics.
-end-
This research was funded by the Canadian Institutes of Health Research and the Scottish Rite Charitable Foundation of Canada.

The Ottawa Hospital is one of Canada's top learning and research hospitals, where excellent care is inspired by research and driven by compassion. As the third-largest employer in Ottawa, our support staff, researchers, nurses, physicians, and volunteers never stop seeking solutions to the most complex health-care challenges. Our multi-campus hospital, affiliated with the University of Ottawa, attracts some of the most influential scientific minds from around the world. Backed by generous support from the community, we are committed to providing the world-class, compassionate care we would want for our loved ones.

The Ottawa Hospital

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.