Scientists still haven’t pinpointed the exact cause of autism. It’s likely that there are multiple factors at play, but recently, research has shown a link between mutations in certain genes related to synaptic function and autism spectrum disorders (ASD).
Being neurodivergent (autistic) means having a brain that works differently from the average or “neurotypical” person. This may be differences in social preferences, ways of learning, ways of communicating and/or ways of perceiving the environment. A newly published brain-tissue study suggests that neurodivergent children 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.
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.
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. All brains start with more connections than they need. The unusually large number in dendritic spines in children with autism may result from deficient pruning early in childhood. Alternatively, the typical pruning process may be overwhelmed by an unusually large number of neuronal connections in the amygdala.
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.
Autophagy allows your body to break down and reuse old cell parts so your cells can operate more efficiently. It’s a natural cleaning out process that begins when your cells are stressed or deprived of nutrients. Researchers are studying autophagy’s role in potentially preventing and fighting disease.
Autophagy is not only the main process in the synaptic pruning function, but it also participates in maintaining the long‐term memory function. Autophagy is a self-cleaning mechanism within our cells, which helps your brain detoxify, repair and regenerate itself. It destroys the old, damaged, and malfunctioning components of your cells – and rebuilds new and healthier ones instead! Early synaptic pruning is mostly influenced by our genes. Later on, it’s based on our experiences. In other words, whether or not a synapse is pruned is influenced by the experiences a developing child has with the world around them. Constant stimulation causes synapses to grow and become permanent. But if a child receives little stimulation the brain will keep fewer of those connections.
Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the same processes may occur in children with autism. “What’s remarkable about the findings,” said Dr. Sulzer, “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.”
The role of mTOR in Autism is involved in various neurodevelopmental processes, including neuronal differentiation, axon guidance, cell migration, and neural region patterning.
A drug that restores normal synaptic pruning can improve autistic-like behaviors in mice, the researchers found, even when the drug is given after the behaviors have appeared. “This is an important finding that could lead to a novel and much-needed therapeutic strategy for autism,” said Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chair of Psychiatry at CUMC and director of the New York State Psychiatric Institute, who was not involved in the study.
Although the drug, 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, PhD, professor of neurobiology in the Departments of Psychiatry, Neurology, and Pharmacology at CUMC.
It is possible that screening for mTOR and autophagic activity will provide a means to diagnose some features of autism, and normalizing these pathways might help to treat synaptic dysfunction and treat the disease.
NOTE FROM CHRISTEL MARITZ
“Neurodiversity” is a word used to explain the unique ways people’s brains work. While everyone’s brain develops similarly, no two brains function just alike. Being neurodivergent means having a brain that works differently from the average or “neurotypical” person. This may be differences in ways of communicating and/or ways of perceiving the environment. Because of this, a neurodivergent person has different struggles and unique strengths.
The paper is titled, Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Other authors are: Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd Rosoklija, AlexanderSosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai Yamamoto, OttavioArancio, Bradley S. Peterson, Frances Champagne, Andrew J. Dwork, and James Goldman from CUMC; and Zhenyu Yue (Icahn School of Medicine at Mount Sinai). Marisa Cotrina is now at the University of Rochester. The authors declare no competing financial interests.