A new study implicates defects in endothelial cells, which are the cells that line blood vessels, as a cause of behavioral symptoms in individuals with a gene disorder linked to autism. In the study, Baptiste Lacoste and his team (including first author Julie Ouellette) studied mice with a 16p11.2 deletion, which is one of the most common genetic mutations seen in individuals with ASD. In addition, they studied cells derived from the tissue of humans with ASD who have this mutation.
Normally, blood flow rapidly increases to areas of the brain where heightened neural activity is occurring, a process called neurovascular coupling. However, in mice with the 16p11.2 deletion, the vascular responses to activated brain regions were slower and weaker.
The researchers found that this problem originated in the blood vessels themselves— and specifically, in the endothelial cells. They also found that the abnormality begins early in life. In petri dish experiments, both human and mouse endothelial cells with the 16p11.2 deletion failed to sprout the extensions that normally allow the vascular network to grow, and the researchers observed the same failure in the endothelial cells of newborn “autistic” mice.
As the mice aged, other cells in the brain compensated for their abnormal endothelial cells, allowing them to develop a full network of blood vessels. However, these vessels remained dysfunctional.
Lacoste comments, “It’s a bit like if a plumber comes to your house and does a bad job installing the pipes. You will have trouble getting the right water pressure in your sink from then on.”
To demonstrate that endothelial problems caused behavioral abnormalities in the mice with the mutation, the researchers created mice that expressed the mutation in their endothelial cells but not in other cells. These mice exhibited the same deficits in vascular development as “whole-body” mutants, and also displayed hyperactivity, stereotypic movements, and motor learning impairments.
The researchers also found that the effects of the 16p11.2 deletion were more pronounced in male mice, indicating that female mice have mechanisms to help compensate for the defect.
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“Vascular contributions to 16p11.2 deletion autism syndrome modeled in mice,” Julie Ouellette, Xavier Toussay, Cesar H. Comin, Luciano da F. Costa, Mirabelle Ho, María Lacalle-Aurioles, Moises Freitas-Andrade, Qing Yan Liu, Sonia Leclerc, Youlian Pan, Ziying Liu, Jean-François Thibodeau, Melissa Yin, Micael Carrier, Cameron J. Morse, Peter Van Dyken, Christopher J. Bergin, Sylvain Baillet, Christopher R. Kennedy, Marie-Ève Tremblay, Yannick D. Benoit, William L. Stanford, Dylan Burger, Duncan J. Stewart, and Baptiste Lacoste, Nature Neuroscience, July 13, 2020 (online). Address: Baptiste Lacoste, blacoste@uottawa.ca.
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“Vascular development may be at risk in autism,” news release, The Ottawa Hospital, July 13, 2020.
This article also appears in Vol. 34, No. 3, 2020, of Autism Research Review International