Neurodevelopmental disorders such as intellectual disability and autism spectrum disorders are marked by mutations that impair signaling between neurons. These mutations cause key brain circuits involved in learning and memory to develop too quickly, leading to long-lasting behavioral and cognitive deficits, according to a study published by Cell Press in the November 9th issue of the journal Cell. The findings could pave the way to new treatment strategies for severe forms of neurodevelopmental disorders.
"We have provided perhaps the first evidence that acceleration of certain neural milestones is just as disruptive as delay in the same milestones," says senior study author Gavin Rumbaugh of Scripps Florida. "These studies have far-reaching implications for how we will treat these severe forms of neurodevelopmental disorders."
Autism spectrum disorders are often accompanied by intellectual disability, and these disorders are linked to harmful mutations that affect proteins responsible for regulating the communication between neurons. A deficiency in one of these proteins, known as SynGAP, can lead to severe forms of these disorders, but it has not been clear how mutations affecting this protein alter the development of brain circuits and behavior.
To answer this question, Rumbaugh and his team inactivated one copy of the SYNGAP1 gene in mice to cause a deficiency in the protein. By two weeks of age, these mice showed a dramatic and premature increase in the communication between neurons in the hippocampus—a critical brain region for learning and memory. As a result, the mice were hyperactive, showed learning deficits, and were prone to seizures, similar to human patients.
These behavioral and cognitive abnormalities persisted even after the researchers restored normal levels of SynGAP in adult mice, suggesting that this protein exerts its effects on cognitive maturation only during a narrow developmental window. Thus, mutations that affect SYNGAP1 can cause neural networks to become miswired early in development and to resist repair during adulthood.
"Our results imply that very early intervention is essential in certain neurodevelopmental disorders, particularly for cognitive symptoms," Rumbaugh says. "We believe that certain pharmacological or genetic treatments initiated in this sensitive developmental window will greatly benefit our model mice, and hence could be translated into patients."
Cell Press: http://www.cellpress.com
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