According to new research at UNC-Chapel Hill, it’s possible that a single biological process plays a role in the origins of both autism and “chemo brain” – the foggy thinking that often accompanies chemotherapy treatments for cancer.
“A lot of times we find strange and unexpected interfaces in the sciences, and this is one of the examples,” said Ben Philpot, professor of cell biology and physiology at UNC and co-lead author of the study along with Mark Zylka, associate professor of cell biology and physiology at UNC.
Philpot, Zylka and their colleagues demonstrated that a common chemotherapy drug halted the activity of synapses, the communication pathways between neurons. When the drug was washed away, synaptic activity resumed.
The neurons in the study were in a lab dish, not a human brain. However, there are clear implications for two seemingly disparate groups of people: cancer patients undergoing chemotherapy, and children with neurodevelopmental disorders such as autism.
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Suppressing synaptic activity could have surprisingly different consequences for the two groups. In fully wired adult brains, the effects might last only as long as the synapses are impaired, and resolve once the synapses recover. “Although this is a speculation, our evidence provides an insight into chemo brain,” Philpot said. “A lot of times when people are given chemotherapy, they report cognitive deficits that improve after the chemo has ended. In the lab, we found when we removed the drug, normal synaptic activity came back.”
In developing brains of babies, however, such a disruption could have effects that persist even after synaptic activity resumes. That’s because in a young brain, synaptic activity plays an essential role in setting up the wiring for such fundamental tasks as interpreting incoming visual stimuli, learning how to recognize the sounds of a native language, and acquiring social skills. In an adult brain, these fundamental neural structures are already in place.
“Impairing synaptic function in a developing brain, even for a relatively short period, can lead to long-lasting effects because of how the brain is wired through a series of critical periods,” said Zylka.
“The critical periods are when the brain is most adept at wiring for certain tasks,” he explained. “Once these connections form, the brain moves on and does other things. The brain can’t go back once a wiring mistake is made.”
The drug Zylka and Philpot studied is a chemotherapy drug called topotecan. It inhibits the formation of an enzyme called topoisomerase, which is necessary for cell division. As a chemo drug, topotecan stops cell division in cancerous tumors.
However, topoisomerase enzymes also play an important role during gene expression, when genes are giving out orders for specific actions, such as producing a protein. When topoisomerase is inhibited, those orders can get garbled.
Many other drugs and chemicals – including some FDA-approved antibiotics and antifungals – also inhibit topoisomerase enzymes.
Building on previous work
In 2013, Philpot and Zylka published a paper in the journal Nature demonstrating that topotecan doesn’t gum up gene expression in all genes – just long ones. To this unexpected result, Zylka added a novel insight that many of the genes implicated in autism are very long.
Zylka wondered whether early exposure to topotecan – or other substances that inhibit topoisomerase production – could cause autism. It’s a timely question, given the soaring rates of autism. According to the latest estimates from the Centers for Disease Control and Prevention, 1 in 68 children in the United States has an autism-spectrum disorder.
The pair decided to follow up on this research, by focusing on a subset of very long genes related to synaptic function. “The question we wanted to address is, if you have this drug that affects synapse genes, is synaptic function impaired?” Zylka said. If topotecan did affect synaptic function, Zylka and Philpot wanted to know how.
To find out, team member and postdoctoral fellow Angela Mabb grew neurons in the lab. The cells spontaneously set up connections among themselves, as neurons are wont to do. Mabb added a dye that fluoresces when the synapses are active. As expected, after two weeks, the synapses were not only active but also synchronized, causing a burst of fluorescence once or twice a minute.
“It’s not identical, but similar to how the neurons would connect up in the brain,” Mabb said. “The bursting activity is basically mimicking what is happening in the human brain.”
Before adding topotecan, she measured the levels of proteins in the cells, including proteins that are created by orders issued by synaptic genes. “These proteins are like glue that connect the cells together to allow them to communicate,” Mabb said.
After she added topotecan to the dish, the bursting stopped. The neurons themselves did not die, but became dormant. Mabb measured levels of the proteins again, and discovered that the levels of the synaptic proteins had plummeted.
When Mabb washed the topotecan out, the synapses recovered their activity in about 24 hours. Levels of the synaptic proteins rose in concert. The surprise? How quickly and fully the synapses recovered. “With the drug shutting down synaptic activity so robustly, the fact that we could reverse that completely was remarkable,” Mabb said.
Zylka’s lab is currently analyzing other drugs and chemicals – including some herbicides and pesticides –to identify those that may interfere with the expression of long genes as topotecan does.
“The thing that motivates me is to better understand the cause or causes of autism,” he said. “The incidence of autism has skyrocketed. There’s speculation that the cause is twofold: One is that there is an increased recognition of autism, and the other is that there is some kind of environmental factor that’s causing an increase. We’re interested in this environmental angle, that chemicals in our environment might perturb brain development and increase the risk for autism.”
The results of the current study were published in Proceedings of the National Academy of Sciences in November. The research was funded by the National Institutes of Health, the Simons Foundation and the Angelman Syndrome Foundation.