Grant: Project Grant

With an elevated energy demand but no energy storage, the growing brain rapidly becomes dependent on a continuous supply of oxygen and nutrients from the blood stream. In addition, the brain must know how to properly transport and use these energy sources. The biological processes that regulate the delivery and utilization of energy sources is known as metabolism. During brain development, the formation of brain cells is well orchestrated to ensure proper growth and function of neural circuits and proper blood perfusion. These "neurovascular" interactions actively regulate energy supply. It is thus expected that defects in blood vessel function occurring early during development may lead to atypical brain maturation, such as seen in autism spectrum disorders (ASD). Neurovascular and metabolic contributions to ASD represent an important knowledge gap. We recently revealed a contribution of vascular deficits to the pathogenesis of the 16p11.2 deletion syndrome, one of the most common genetic causes of ASD. But the question remains on how vascular cells regulate their metabolism in response to this mutation. We identified altered brain metabolism in an ASD mouse model, and we now hypothesize that the 16p11.2 deletion triggers major changes in vascular metabolism, which can be measured but also targeted for treatment in mouse models. We have recently obtained preliminary (unpublished) results supporting this idea. To test our novel hypothesis, we assembled a team of experts who will use advanced technologies to: i) Thoroughly investigate the effects of the 16p11.2 deletion on vascular metabolism; ii) Elucidate the mechanisms responsible for the metabolic failure of vascular cells; and iii) Test whether treatment to ameliorate vascular health can improve ASD symptoms in mice. By following these three objectives, we aim to fill an important gap in ASD research, providing new insight into pathogenesis of ASD, and exploring new treatment avenues.