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Metabolic Drivers of Circuit Dysfunction in ASD: A Conceptually and Technically Novel Approach

Neurons are one of the most energetically “expensive” cells in our body because they need to constantly fuel neuronal activity and because they release large amounts of neurotransmitters. Accordingly, energetic defects, as often seen in metabolic diseases (e.g., diabetes), are tightly associated with neurological disorders, including ASD. The degree to which a metabolic defect impacts the initiation and progression of ASD has been a major source of debate in the field. The technical hurdles to tackle this important question are the following: 1) the field lacks experimental tools to precisely monitor both neuronal activity and metabolic readouts in specific types of neurons in awake animals, 2) there are numerous distinct populations of neurons within the cortex that play unique roles in driving brain pathology, yet we haven’t been able to target those specific populations with sufficient precision, and 3) we lack the computational power to integrate large amounts of data from culture cells, animal models, and humans to optimally guide therapeutic strategies.

The multidisciplinary team of Andermann and Kajimura labs will overcome the above hurdles by employing innovative tools, including novel imaging systems in awake animals, state-of-the-art bioenergetic platforms, and AI-based data integration tools that each lab has established. With these novel tools in hand, the PIs aim to test the hypothesis that unusually high rates of “unpredictable” sensory stimuli in ASD-relevant cortical neurons trigger mitochondrial impairment, hyperexcitability, and the overproduction of toxic metabolites, which leads to a negative spiral of impaired ability of the brain to properly anticipate sensory stimuli. They predict that this dysregulation of neuronal metabolism and hyperexcitability could be blocked or reversed by supplementing alternative fuel sources to the neurons in conjunction with other novel therapeutic approaches, thereby breaking the negative spiral. If this prediction holds true, the PIs anticipate that their approach linking metabolism and neural activity could be applied in human subjects to effectively reduce the development and severity of sensory hypersensitivity and other symptoms common in ASD. Their approach begins with deepening our fundamental understanding of the basic mechanisms, i.e., how the regulatory pathways of neuronal metabolism go awry in animal models and in humans with ASD. The researchers believe that a precise molecular underpinning will pave a new path toward therapeutic intervention.