Recent scientific studies have demonstrated how the brains of children with autism are hyper-connected in ways related to the severity in each individual. Now, a new study from Columbia University Medical Center (CUMC) extends the research in this area by revealing how children and teens with autism have a surplus of synapses — the points where neurons connect and communicate with each other — and this excess is due to a slowdown in the normal "pruning" process of brain development.

In mice, the drug rapamycin can restore normal synaptic pruning, the researchers found, and improve autistic-like behaviors even when the drug is given after autistic behaviors appear. Though rapamycin has side effects rendering it unsafe for children, the drug still offers hope. "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 Dr. David Sulzer, professor of neurobiology and senior author of the study.

Normal vs. Autistic Brain Development

“While people usually think of learning as requiring formation of new synapses, the removal of inappropriate synapses may be just as important,” Sulzer said. In fact, our brains incorporate "pruning" — the horticultural practice of removing diseased and dead plants — into normal development. During infancy, a burst of synapse formation occurs, particularly in the cortex, a region linked to autistic behavior. The pruning which occurs in a normal brain eliminates about half of these cortical synapses by the late teen years.

To test the hypothesis that people with autism have more synapses than normal, the research team at CUMC examined the brains of children with autism who had died from other causes. By comparison, 22 brains from children without autism were examined along with the 13 brains of children who died between ages 2 and 9, and the 13 brains of children who died between the ages of 13 and 20. How did the researchers measure synapse density in the cortical region of each brain? They simply counted the number of tiny spines branching from each neuron; each spine connects with another neuron via a synapse.

By late childhood, the researchers discovered, spine density had dropped by about half in the normal brains, but only by about 16 percent in the autistic brains. "It's the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism," Sulzer said.

Clues to what might have caused defective pruning were also found. The autistic children’s brain cells were filled with old and damaged parts. In fact, they were deficient in a pathway known as "autophagy" (a term from the Greek meaning self-eating), a process by which cells perform their housekeeping work. Following this discovery, the CUMC research team explored for more details as to what exactly had occurred in these autistic brains. Using mouse models, the researchers traced the pruning defect to a single protein called mTOR. When mTOR is overactive, brain cells lose much of their "self-eating" ability.

By administering rapamycin, a drug that inhibits mTOR, the researchers found they could restore normal autophagy and synaptic pruning — and even reverse autistic-like behaviors in the mice. Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the researchers believe the same processes may be occurring in children with autism. "What's remarkable about the findings is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy,” Sulzer said. “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.”

Source:  Lieberman J, Sulzer D, Gudsnuk K, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014.