Drugs that increase insulin signaling may be effective in treating autism, say Lancaster University researchers who have discovered how genetic changes affect insulin signaling and glucose metabolism in the brain.
In the human genome, some have found that small sections of DNA are duplicated or deleted, a phenomenon known as copy number variation. Some of these genetic changes can lead to neurodevelopmental problems and significantly increase someone’s risk for conditions such as autism, schizophrenia and Tourette’s syndrome.
For example, people with a deletion of the Neurexin1 gene due to a DNA deletion of chromosome 2p16.3 often experience neurodevelopmental delays and cognitive problems. People with a 2p16.3 deletion are also 14 to 20 times more likely to develop neurodevelopmental disorders, including autism, schizophrenia, and Tourette syndrome, than people without the deletion. An estimated 2 to 3 million people worldwide suffer from this type of DNA deletion, but there are currently no effective drug treatments to treat their resulting cognitive problems.
In research funded by the Royal Society, scientists have demonstrated for the first time that loss of the Neurexin1 gene reduces glucose metabolism in the prefrontal cortex, a key brain region involved in higher-level cognitive functions, including cognitive flexibility and attention. Neurexin1 deletion was also found to reduce insulin receptor signaling in the prefrontal cortex, which may underlie reduced glucose metabolism in this region.
The study, published in the journal Autism Research, provides valuable new insights into how this leads to cognitive deficits, behavioral changes, and significantly increases the risk of a range of neurodevelopmental disorders.
The key finding that Neurexin1 deletion affects insulin signaling and glucose metabolism in the prefrontal cortex suggests that the use of drugs to increase insulin signaling may be an effective therapeutic strategy.
Lead researcher Dr Neil Dawson, from Lancaster University, said: “There is an urgent need to further understand the underlying neurobiology of neurodevelopmental disorders so that new treatments can be developed. Drugs that help people with cognitive and social problems are particularly urgently needed. , because these symptoms greatly impact their quality of life.”
In addition, the researchers showed that loss of Neurexin1 leads to deficits in prefrontal cortex-dependent cognitive function, including deficits in flexibility. The study also found that the reduced glucose metabolism in the prefrontal cortex caused by the loss of Neurexin1 was associated with hyperactivity when confronted with new situations.
The second brain region identified as being affected by the loss of Neurexin1 was the dorsal raphe, which had increased activity. This region is the origin of serotonin neurons that spread throughout the brain, suggesting that loss of Neurexin1 also makes the serotonin neurotransmitter system dysfunctional.
Dr Neil Dawson said: “Furthermore, the observation that the serotonin system may be dysfunctional requires further study and suggests that drugs targeting this neurotransmitter system may also be useful. We can now test drug recovery by targeting these mechanisms. The capabilities of these mechanisms. Translational changes are seen as part of ongoing research aimed at developing better treatments for people with 2p16.3 deletions, autism, schizophrenia and Tourette’s syndrome.”
