New research has found that genetic change associated with cognitive deficits and risk of certain neurodevelopmental disorders affects brain function, raising the possibility of new drug treatments

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Scientists from Lancaster University have discovered, for the first time, how a genetic change associated with cognitive deficits and risk of certain neurodevelopmental disorders affects brain function, raising the possibility of new drug treatments for neurodevelopmental disorders such as autism.

For their research, published in Autism Research, the scientists explored Neurexin1 gene expression, and demonstrated how reduced expression of this gene in mice impacts on the prefrontal cortex and impairs cognitive flexibility.

Specifically, they demonstrated that Neurexin1 gene deletion reduces glucose metabolism in the prefrontal cortex, the area involved in higher-level cognitive functions including paying attention and cognitive flexibility. They also found that the reduced glucose metabolism in the prefrontal cortex resulting from the deletion was linked with male mice becoming hyperactive when experiencing novel situations.

The authors said that people with a DNA deletion at chromosome 2p16.3, which results in deletion of the Neurexin1 gene, often experience neurodevelopmental delay and cognitive problems. Those with the 2p16.3 deletion are around 14 to 20 times more likely to develop neurodevelopmental disorders, such as autism, than people without the deletion.

Effective drug treatment needed

It is known that some genetic changes both cause neurodevelopmental problems and dramatically increase the risk of a person developing disorders such as autism, schizophrenia, and Tourette’s syndrome. However, even though there are an estimated 2–3 million people worldwide who have this type of DNA deletion, ‘there are currently no effective drug treatments for their resulting cognitive problems’, the authors said.

In addition to demonstrating that Neurexin1 gene deletion reduces glucose metabolism in the prefrontal cortex, they also found that it reduces insulin receptor signalling in the prefrontal cortex. This, they said, ‘likely underlies the reduced glucose metabolism seen in this region’.

Their findings open the door for potential new drugs that increase insulin signalling to be used to treat autism and other neurodevelopmental disorders.

Lead researcher Dr Neil Dawson, from Lancaster University, said: ‘There is an urgent need to further understand the underlying neurobiology of neurodevelopmental disorders in order to develop new treatments.’

The key finding that Neurexin1 deletion impacts on insulin signalling and glucose metabolism in the prefrontal cortex suggests that using drugs to increase insulin signalling may be an effective therapeutic strategy.

Dr Dawson emphasised that drugs to help people with their cognitive and social problems are particularly urgently needed, as these symptoms dramatically impact on a person’s quality of life.

Dysfunctional serotonin neurotransmitter system

The scientists identified a second brain region impacted by Neurexin1 deletion—the dorsal raphé, which showed increased activity. This region, they explained, is the origin of serotonin neurons that project throughout the brain. This suggests that Neurexin1 deletion also makes the serotonin neurotransmitter system dysfunctional.

Dr Dawson said: ‘The observation that the serotonin system may be dysfunctional requires further research and suggests that drugs targeting this neurotransmitter system may also be useful.’

The authors concluded that targeting the prefrontal cortex and serotonin system may be useful therapeutic strategies for individuals with 2p16.3 deletion and the neurodevelopmental disorders associated with it.

Dr Dawson said: ‘We can now test the ability of drugs that target these mechanisms to restore these translational changes seen as part of ongoing research to develop better treatments for people with 2p16.3 deletion, autism, schizophrenia, and Tourette’s syndrome.’

This article originally appeared on Medscape, part of the Medscape Professional Network.

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