Autism as a brain energy disorder: How impairments in brain glucose metabolism give rise to autism symptoms

Autism spectrum disorder (ASD) is a neurodevelopmental condition that is characterized by social communication deficits, restricted and repetitive behavioral patterns, and sensory abnormalities. In this review, we posit that the core ASD symptoms originate from impaired brain energy metabolism, specifically within astrocytes, which play a key role in glucose uptake, glycogen storage, and energetic support for neurons. Neuronal signaling depends on a continuous supply of adenosine triphosphate (ATP), and glucose constitutes the principal energy substrate of the brain. Therefore, disrupted glucose delivery or utilization can significantly affect ATP availability in neurons and other brain cells, which can influence brain development and function. We hypothesize that ASD may represent a form of “energy-saving adaptation”, wherein the brain economizes energetically by deprioritizing higher-order, energy-intensive processes, such as social communication, adaptation to novel information, cognitive flexibility, and sensory integration, and preserves ATP for basic survival functions. Building upon a comprehensive synthesis of the relevant literature, we argue that deficits in cellular metabolism in the brain, and subsequent suboptimal ATP generation and/or utilization, underlie ASD symptomatology, regardless of etiology. The conceptualization of ASD as a disorder of brain energy metabolism could catalyze new research agendas via cross-pollination of findings from related fields such as diabetes-linked cognitive dysfunction, schizophrenia, bipolar disorder (BP), and other neuropsychiatric and neurological conditions that implicate brain energy metabolism as a key pathogenic factor.