Many children with autism have unusually high numbers of synapses, or connections between neurons, particularly in the cortex, which may result from overgrowth and a disruption of neuronal pruning during childhood. Pruning and reshaping of neurons pares down the number of synapses in the brain while eliminating inappropriate synapses that lead to over-connectivity between brain regions, and possibly inappropriate learning, behavior and seizures. David Sulzer and his colleagues at Columbia University hypothesize that autism-associated mutations in the tuberous sclerosis gene, TSC, can cause over-connectivity when the target of TSC, the mTOR pathway, interferes with normal neuronal pruning.

Neuronal pruning largely occurs by the cell’s breakdown of internal components, a process called macroautophagy. The mTOR pathway turns off macroautophagy, but macroautophagy can proceed upon inhibition of mTOR by TSC proteins. The researchers hypothesize that autism-linked mutations in TSC deregulate mTOR, allowing the pathway to inhibit macroautophagy in neurons, which could then lead to neuronal overgrowth and over-connectivity.

To test this hypothesis, the researchers are studying macroautophagy in the synapses of mice deficient of TSC, which should deregulate mTOR, and of mice deficient of macroautophagy genes, which should also prevent pruning. They plan to examine brain structures for atypical pruning or neuronal overgrowth in these mice. They also plan to use these mice to determine whether deregulation of mTOR results in abnormal increases in cortical synapses and neuronal activity. In parallel, the researchers also plan to investigate whether the brains of individuals with autism show changes in synapses consistent with the effects detected in the mutant mice.

The researchers further propose to test whether rapamycin, a drug that inhibits the mTOR protein, could compensate for the loss of the TSC proteins in mice. If rapamycin can restore normal levels of macroautophagy and synaptic pruning in TSC-deficient mice, perhaps a similar drug would be beneficial in individuals with autism who have mutations in the mTOR-related pathways.