Neurite Overgrowth
When mTORC1 is normally active, it promotes the extension of neurites—the precursors to axons and dendrites. However, under conditions of hyperactivation, this process goes into overdrive. Neural Stem Cells (NSCs) derived from ASD patients often display shorter, more branched, and disorganized neurites. This "bushy" phenotype impairs the cell's ability to migrate correctly and form precise connections, leading to the disorganized cortical layering seen in autistic brains.
Synaptic Failure
A hallmark of learning is the ability to prune unnecessary connections—a process called synaptic pruning. This "trimming of the fat" is essential for efficient information processing. mTOR hyperactivation inhibits autophagy, the cellular "recycling" process required for pruning. Specifically, elevated mTOR inhibits the ULK1 complex, blocking the formation of autophagosomes. The result is a failure to degrade old or weak synapses. This leads to a dense, noisy brain with too many connections, contributing to the sensory overload and cognitive rigidity often experienced by individuals with ASD.
Excitation/Inhibition Imbalance
The effects of mTOR hyperactivation are not uniform across all cell types. Excitatory glutamatergic neurons appear to be more sensitive to elevated mTOR than inhibitory GABAergic neurons. This differential sensitivity exacerbates the "Excitation/Inhibition (E/I) imbalance" hypothesis of autism. The overgrowth of excitatory spines, coupled with a relative lack of inhibitory control, creates a hyperexcitable circuit prone to seizures—a common comorbidity in autism—and sensory hypersensitivity.
The Autophagy Blockade
Beyond pruning, autophagy is critical for removing damaged proteins and organelles. In ASD neurons with high mTOR, autophagy is suppressed, leading to the accumulation of cellular debris and misfolded proteins. This cellular stress triggers a chronic inflammatory state within the brain (neuroinflammation), further impairing neuronal function. Thus, mTOR hyperactivation delivers a double blow: it builds too much "noise" (synapses) and prevents the "cleaning crew" (autophagy) from doing its job.
Excerpt from: Utilizing mTOR Inhibitors as Synergistic Modulators in Augmenting Stem Cell Therapy for Autism Spectrum Disorder by Peter De Ceuster
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