Blocking key pathway reverses mind, habits adjustments in autism mouse mannequin | Spectrum
Extra spines: Mice with an extra copy of the MECP2 gene develop more spines on their motor cortex neurons (top) than wild-type mice during a learning task. An experimental drug normalizes this property (below).
Neurons in mice with an autism-related mutation sprout outward protrusions, an overgrowth that is tracked with above-average motor learning. According to a new study, the animals lose both traits when treated with an experimental drug that suppresses the activity of the Ras-ERK / MAPK cell signaling pathway.
This pathway helps reshape neurons to change the strength of their connections in response to learning or other influences, part of a process known as neuroplasticity.
“There is a balance in the brain between learning and forgetting,” says lead researcher Stelios Smirnakis, associate professor of neurology at Harvard University. “Understanding these pathways and how to balance them is critical to a number of neurological disorders.”
Hyperactivation of the Ras-ERK / MAPK signaling pathway, which is also involved in cell growth, has been linked to cancer and several autism-related diseases.
“Many genes in this pathway have been shown to underlie several forms of autism,” said Maria Chahrour, assistant professor of neuroscience at Southwestern Medical Center at the University of Texas at Dallas, who was not involved in the study. “The path itself is also dysregulated in several forms of autism, so there is potential convergence.”
The mice in the new work had an additional copy of the MECP2 gene. As in previous studies and some other autism mouse models, the MECP2 duplication mice demonstrated improved motor learning and mastered balancing on a rotating stick faster than their wild-type counterparts. The animals’ motor learning abilities provide a model for studying how repetitive behaviors develop in people with autism, the researchers say.
Smirnakis and his colleagues used two-photon microscopy to map neurons in the animals’ motor cortex before and after the four-day training session on the rotating rod test.
The training caused the neurons in the MECP2 mice to form excess dendritic spines – small projections on neurons that receive signals from other neurons.
Thorns are usually evenly distributed along dendrites. But in the MECP2 mice, they were more likely to occur in dense clusters, a sign that the animals were forming stable memories, says study researcher Ryan Ash, who works in psychiatry and behavioral sciences at Stanford University in California.
The Ras-ERK / MAPK pathway is involved in the formation of spines and was significantly more active in the MECP2 mice after training, as the study also shows.
“This work adds to the growing evidence that ERK signaling is likely to play a central role in autism in general, and offers a new mechanistic explanation of the possible ways ERK signaling is involved in the phenotype of autism,” says Ning Cheng, Associate Professor of Neuroscience at the University of Calgary in Alberta, Canada, who was not involved in the study.
The work was published in eNeuro in May.
Treatment of the MECP2 mice with a drug called SL327, which inhibits the Ras-ERK / MAPK pathway, restored typical motor learning and dendritic spine growth.
The drug’s effects only last about two hours, so it is unlikely to be a viable treatment for humans. But some cancer drugs and cholesterol-lowering drugs called statins block the same path and could have therapeutic potential, says Smirnakis.
“I fully agree with the authors that targeted ERK signaling could prove to be a fruitful approach to treating autism,” says Cheng. A crucial part of that strategy will be identifying inhibitors that cross the blood-brain barrier and have no major side effects, she says.
Part of that search for treatments could be to analyze exactly what part of the signaling pathway is dysregulated in individuals, leading to more personalized therapies that target only the relevant goals, says Ash.
“This is a very essential path, and if you want to inhibit it, you have to be careful what else happens and that there are no other compensation mechanisms,” says Chahrour.
SL327 did not appear to have a significant effect on spinal column formation in wild-type mice, suggesting a low risk of off-target effects, says Ash.
The team has built a library of signaling pathways involved in neuroplasticity that could be involved in autism and other conditions, as well as typical learning, says Smirnakis. They want to find out which of these pathways contribute to learning in MECP2 duplication mice and test their role in certain cell types.
Quote this article: https://doi.org/10.53053/WRGS1140