Hippocampal Neuronal Overflow: A Novel Etiological Hypothesis for Autism Spectrum Disorders

The prevalence of autism spectrum disorders (ASD) continues to rise, and while existing gene-environment interaction theories provide a research framework, they have yet to reveal the true etiology. This may stem from an inadequately understood key factor: the unique developmental mechanisms of human cerebral cortex. To attempt to fill this potential gap, we propose the "hippocampal neuronal overflow hypothesis," which explains ASD etiology through the lens of uniquely human neural developmental processes: during the peak period of hippocampal neurogenesis from the human perinatal stage to approximately 18 months post-birth, newborn neurons are generated in large quantities under stimulation from environmental information and learning tasks, gradually accumulating and breaking through hippocampal capacity limitations, resulting in "neuronal overflow" that enters the white matter and migrates with migratory streams into the forebrain cortex. These moderately overflowing neurons form new anatomical structures in the forebrain cortex, providing a unique structural foundation for language and higher cognitive development. However, when environmental information and learning task stimulation becomes excessive, the excessive overflow of immature neurons forms dense connections within the forebrain cortex, and their connection tension disrupts the dendrites and longitudinal axons of normal cortical neurons, leading to local hyperconnectivity and cortical functional deficits, ultimately manifesting as core ASD symptoms. This hypothesis can explain the timing of ASD symptom onset, the distribution of damaged cortex, and individual differences, suggesting that ASD may originate from overexpression of uniquely human developmental mechanisms rather than single genetic or environmental factors. If this hypothesis is validated, ASD could potentially transform from a difficult-to-prevent genetic disease into a preventable developmental phenomenon through regulation of early information intake.