Brain Study Finds Evidence that Autism Involves Too Many Synapses
Researchers propose that someday it may be possible treat autism with drugs that restore normal pruning of brain-cell connections
August 21, 2014
A newly published brain-tissue study suggests that children affected by autism have a surplus of synapses, or connections between brain cells. The excess is due to a slowdown in the normal pruning process that occurs during brain development, the researchers say.
The study team also found that the medication rapamycin both restores normal synaptic pruning and reduces autism-like behaviors in a mouse model of autism. They propose that someday a similar medication might be used to treat autism after a child – or even adult – has been diagnosed.
The report, by neuroscientists at Columbia University Medical Center, appears in the journal Neuron.
Autism Speaks is currently funding several studies on rapamycin. It is also supporting a treatment study using a medication with a very similar action for treatment of autism associated with tuberous sclerosis complex (TSC). This rare syndrome often, but not always, involves autism. Indeed, the laboratory mice used in the new Columbia study were developed as an animal model of this syndrome.
“There are many unknowns in translating research from mice to humans,” comments Paul Wang, Autism Speaks senior vice president and head of medical research. “But the data from mice suggest that such medicines could have a positive effect on behavior and cognition in patients with TSC. The findings of this newest study might also be relevant to a subset of other patients with autism.” Dr. Wang was not involved in the new Columbia study.
The insights from the new study also underscore the vital importance of post-mortem brain donations in advancing research on autism treatments, Dr. Wang adds.
Autism Speaks actively supports autism brain banking through Autism BrainNet.
The vital process of brain pruning
During normal brain development, a burst of synapse formation occurs in infancy. This is particularly pronounced in the cortex, which is central to thought and processing information from the senses. But by late adolescence, pruning eliminates about half of these cortical synapses.
In addition, many genes linked to autism are known to affect the development or function of brain synapses. Indeed, the idea that individuals with autism have excess synapses has been proposed before.
To test this hypothesis, Columbia researcher Guomei Tang analyzed brain tissue from 26 children and young adults affected by autism. Thirteen of the children were between the ages of 2 and 9 when they died. Thirteen were between 13 to 20. For comparison, she also examined donated postmortem brain tissue from 22 children and teens who did not have autism.
Dr. Tang measured the abundance of synapses in a small section of cortical tissue from each brain. She found that, by late childhood, the density had dropped by about half in the brain tissue unaffected by autism. By contrast, it was reduced by around 16 percent in the brains from individuals who had autism.
She also found clues to what may have caused the lack of pruning. The brain cells from the individuals with autism were filled with damaged parts and deficient in signs of a normal breakdown pathway called “autophagy.” Cells use autophagy (Greek for “self-eating”) to breakdown components – include synapse connections.
Applying findings to mouse models
Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR. When mTOR is overactive, they found, brain cells lose much of their self-pruning ability. As a result, the brain cells show an overabundance of synapses.
The researchers restored normal autophagy and synaptic pruning in the mice by administering rapamycin – a drug that inhibits mTOR. Treatment eliminated the mice’s autism-like behaviors. The treatment remained effective even when administered to older mice that had fully developed the autism-like behaviors.
The researchers cite this as hopeful evidence that similar treatments might someday be used to treat autism after symptoms have fully emerged. As further evidence, the researchers found large amounts of overactive mTOR in the postmortem brain tissue of the individuals with autism.
Though hundreds of genes have been linked to autism, the researcher conclude, many if not most of them may affect this mTOR/autophagy pathway.