Children and adolescents with autism have a surplus of synapses in the brain that may have profound effects on how the brain functions, a study by neuroscientists at Columbia University Medical Center finds.
Funded by the Simons Foundation, with additional support from the U.S. Department of Defense and the Parkinson's Disease and JPB foundations, the study found that while the synapse density in neurotypical brains declines by 50 percent by late childhood, the decline in synapse density in the brains of youth with autism was only 16 percent. Using mouse models of autism, researchers traced this so-called "pruning" defect to a protein called mTOR. When mTOR is overactive, brain cells lose much of their autophagy ("self-eating") ability. Without that ability, the brains of the mice ended up being poorly pruned and contained excess synapses.
Researchers also found that they could restore normal autophagy and synaptic pruning — and reverse autistic-like behaviors in the mice — by administering rapamycin, a drug that inhibits mTOR. The drug was effective even when administered to the mice after they developed autistic-like behaviors, suggesting that such an approach could be used to treat the disorder after it has been diagnosed. Although rapamycin has side effects that may preclude its use in people with autism, "the fact that we can see changes in behavior suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug," said the study's senior investigator, David Sulzer, Ph.D., professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at CUMC.
"What's remarkable about the findings," Sulzer added, "is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River. Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism."
Alan Packer, senior scientist at the Simons Foundation, said the study is an important step in understanding what's happening in the brains of people with autism. "The current view is that autism is heterogeneous, with potentially hundreds of genes that can contribute," said Packer. "That's a very wide spectrum, so the goal now is to understand how those hundreds of genes cluster together into a smaller number of pathways; that will give us better clues to potential treatments."