Cellular and Molecular Mechanisms of Altered Brain Metabolism in Autism Mice: Toward Earlier Diagnosis and Treatment
Abstract
With an elevated energy demand but a low capacity to store the energy, the growing brain rapidly becomes dependent on a continuous supply of oxygen and energy sources (nutrients like glucose) from the blood stream. In addition, the brain must know how to properly use these energy sources. The ensemble of biological processes put in place to regulate the delivery and utilization of energy sources is known as metabolism. During brain development, the formation of new neurons, blood vessels and glial cells is well orchestrated to ensure proper blood perfusion, as well as growth and function of neural circuits. These neuro-vascular interactions actively regulate energy supply to meet energy usage and to sustain brain function, a phenomenon named metabolic homeostasis. In a typical brain, the interdependence between blood vessels, glial cells and neurons allows harmonious brain maturation. However, it is expected that defects in metabolism occurring early during development (for example due to genetic mutations) may lead to atypical brain maturation, such as seen in autism spectrum disorders (ASD). ASD are neurodevelopmental conditions characterized by intellectual disabilities, speech and language problems, repetitive movements, highly focused interests, as well as differences in brain structure. For decades, researchers focused almost exclusively on studying neuronal deficits in ASD. As such, neuro-vascular and metabolic contributions to ASD represent an important knowledge gap. A recent finding from our laboratory revealed a surprising contribution of vascular deficits to the pathogenesis of the 16p11.2 deletion syndrome, one of the most common genetic causes of ASD. While this represented a major discovery in ASD research, the question remains on how the ASD brain regulates its metabolic homeostasis in response to neuro-vascular anomalies. While metabolic disturbances have been found in ASD patients, altered brain metabolism in ASD remains to be elucidated. We hypothesize that the 16p11.2 deletion triggers a major change in brain metabolism that can be measured but also targeted for treatment of ASD-related behavioral deficits in mice. We have recently obtained new (unpublished) results supporting this idea. To test our hypothesis, we assembled a team of experts who will use advanced technologies to: 1. Quantify brain metabolism in a mouse model of the 16p11.2 deletion syndrome. 2. Investigate the effect of the 16p11.2 deletion on brain cells isolated from mouse brains. 3. Test whether treating mice to compensate for defective brain metabolism can ameliorate ASD symptoms. By following these three objectives, we aim to fill an important gap in ASD research, providing new insight into pathogenesis of ASD, and exploring novel treatment avenues. As most studies have focused on neuronal aspects of ASD, our research perspectives represent a paradigm shift, as a first attempt to investigate brain metabolism in relation to non-neuronal deficiencies in a robust ASD mouse model. Identification of new disease mechanisms is an essential step in the development of new therapies and diagnostics for ASD, which is desperately needed for the ASD population and their relatives. About 1 in 54 U.S. children received an autism diagnosis (Centers for Disease Control and Prevention, 2020). In the U.S., costs for supporting an individual with ASD during her/his lifespan have been estimated at $2.4 million in 2014, for a shocking national economic burden of ~$250 billion per year. As no cure exists to treat ASD, exploring novel avenues for ASD care represents an urgent clinical need.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210583
Entities
People
- Baptiste Lacoste
Organizations
- United States Army
- University of Ottawa