Researchers have steadily been uncovering the neuronal underpinnings of autism spectrum disorder (ASD). However, the role of some factors remains elusive, including the vascular contributions to ASD. Now, a team has undertaken the first-ever in-depth study of vasculature in the autistic brain. The study lays out several lines of novel evidence that strongly implicate defects in endothelial cells—the lining of blood vessels—in autism.
The research relied on a mouse model with one of the most common genetic mutations found in ASD—the 16p11.2 deletion. The team investigated postnatal cerebrovascular development in the 16p11.2df/+ mouse model of 16p11.2 deletion ASD syndrome. They also used cells derived from the tissue of human autistic adults who carry the 16p mutation.
The work is published in a paper titled, “Vascular contributions to 16p11.2 deletion autism syndrome modeled in mice,” in Nature Neuroscience.
“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,” said Baptiste Lacoste, PhD, assistant professor and scientist in the neuroscience program, Ottawa Hospital Research Institute and senior author on the study. “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, blood rushes to the active brain region in a process called “neurovascular coupling.” But when neurons of mice with the 16p deletion are stimulated, 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 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.
The researchers found that problems with blood vessels begin very early in life for those who carry the 16p deletion, and that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. 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.
The authors noted that, in 16p11.2df/+ mice, “endothelial dysfunction results in impaired cerebral angiogenesis at postnatal day 14, and in altered neurovascular coupling and cerebrovascular reactivity at postnatal day 50.”
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,” said Lacoste. “You will have trouble getting the right water pressure in your sink from then on.”
In addition, they showed that there is defective angiogenesis “in primary 16p11.2df/+ mouse brain endothelial cells and in induced-pluripotent-stem-cell-derived endothelial cells from human carriers of the 16p11.2 deletion.”
Blood vessels and autistic behavior
To pin down the cause of systemic developmental differences from a 16p mutation, the team generated mice that only expressed the mutation in their endothelial cells. 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 wild-type, these conditional mutants displayed some behavioral 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. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, the team’s results “point to a potential role for endothelial impairment in ASD.”
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 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.
