New Insight Into Autism and a Potential New Treatment
Kids with autism have too many synapses in an area of the brain that undergoes rapid development during early childhood. According to new research by investigators at Columbia University Medical Center, this period of early development is normally accompanied by a robust system that “prunes” new connections. These connections, or synapses, represent the many points where brain nerve cells (neurons) link together and communicate. Having too many of these connections drastically alters brain function, say neuroscientists.
It’s unclear why the normal pruning process slows down so dramatically among children with autism, although genes evidently play a role, but investigators believe it may be possible to reverse some of the effects of this deficit by administering a drug that restores pruning activity to a more normal level.
Synaptic pruning is believed to be an important step in early brain development. Among normal children, up to 50 percent of connections are pruned during this early development phase. But among autistic children, just 16 percent of these connections are severed. Autistic brains also show signs of a dramatically decreased ability to remove old cellular debris; a process called autophagy. This process works a little like a city sanitation department. “Trash” is regularly removed (and sometimes recycled) from city streets, keeping things moving along in an orderly, sanitary fashion.
Think of the developing brain as a group of rapidly growing shrubs in a well-tended garden. If the gardener is vigilant, he will carefully control the explosive growth of the shrubs in his garden, judiciously trimming back here, allowing growth there; discouraging one branch’s growth, while encouraging the growth of an adjacent branch. In the end, the shrubs are healthy, upright, and free of disease. The gardener may move with ease among the various well-tended shrubs, with plenty of light and water available for all.
But in the “autistic” garden, the gardener neglects his duties. The shrubs rapidly grow scraggly, with their limbs intertwining. It become difficult, if not impossible, to navigate the paths among the shrubs, while some begin to die back due to lack of light and competition for water and nutrients. The garden is no longer useful as a calm, cool retreat, because of riotous overgrowth that prevents anyone from entering. There is no order; just a tangled mass of branches that make it difficult to distinguish between one shrub and another.
The pruning activity that occurs in the developing brain is related to a protein called mTOR. It’s overactive among autistic people, with the result that autophagy of cellular garbage is inhibited. But a common drug, rapamycin, is known to inhibit mTOR. So, investigators speculate, rapamycin or a less toxic drug with similar activity, could be given to autistic patients to boost autophagy activity, which would “clean the streets” in the brain, hopefully reducing autism symptoms. It’s worked in mice, so far, but remains to be tested in humans.
“What’s remarkable about the findings,” said David Sulzer, PhD, in a press release, “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…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.”
Guomei Tang, Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai Yamamoto, Zhenyu Yue, Ottavio Arancio, Bradley S. Peterson, Frances Champagne, Andrew J. Dwork, James Goldman, David Sulzer. Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Neuron, 2014; DOI: 10.1016/j.neuron.2014.07.040
Columbia University Medical Center. "Children with autism have extra synapses in brain: May be possible to prune synapses with drug after diagnosis." ScienceDaily. ScienceDaily, 21 August 2014.