Summary: Deletion of Neurexin1 impacts insulin signaling and glucose metabolism in the prefrontal cortex. Researchers say that increasing insulin signaling may be an effective therapeutic strategy for treating ASD.
Source: Lancaster University
Drugs to increase insulin signaling may be effective in treating autism, say Lancaster University researchers, who found impact of genetic change on insulin signaling and metabolism glucose in the brain.
In the human genome, small sections of DNA have been shown to be duplicated or deleted in some people, a phenomenon known as copy number variation.
Some of these genetic changes cause neurodevelopmental problems and greatly increase the risk of developing disorders such as autism, schizophrenia and Tourette syndrome.
For example, people with a DNA deletion at chromosome 2p16.3, which results in the deletion of the Neurexin1 gene, typically suffer from neurodevelopmental delay and cognitive problems.
People with the 2p16.3 deletion are also about 14 to 20 times more likely to develop neurodevelopmental disorders, including autism, schizophrenia and Tourette’s syndrome, than people without the deletion.
It is estimated that two to three million people worldwide suffer from this type of DNA deletion, but there is currently no effective drug treatment for the resulting cognitive problems.
For the first time, in research funded by the Royal Society, scientists have demonstrated that deleting the Neurexin1 gene reduces glucose metabolism in the prefrontal cortex, a key brain region involved in higher-level cognitive functions, including flexibility cognitive and attention. Deletion of Neurexin1 was also found to reduce insulin receptor signaling in the prefrontal cortex, which likely underlies the reduced glucose metabolism observed in this region.
The research, 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 developing a range of neurodevelopmental disorders.
The key finding that deletion of Neurexin1 impacts insulin signaling and glucose metabolism in the prefrontal cortex suggests that using 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 better understand the underlying neurobiology of neurodevelopmental disorders in order to develop new treatments. Medications to help people with cognitive and social issues are particularly needed, as these symptoms have a significant impact on their quality of life.
Additionally, the researchers also showed that deletion of Neurexin1 leads to deficits in cognitive functions that depend on the prefrontal cortex, including a deficit in the ability to be flexible.
Research also found that the reduction in glucose metabolism in the prefrontal cortex resulting from the deletion of Neurexin1 was linked to hyperactivity during novel situations.
A second brain region identified as being impacted by the deletion of Neurexin1 was the dorsal raphe, which showed increased activity. This region is the source of serotonin neurons that project throughout the brain, suggesting that deletion of Neurexin1 also renders the serotonin neurotransmitter system dysfunctional.
Dr Neil Dawson said: “Furthermore, the observation that the serotonergic system may be dysfunctional requires further research and suggests that drugs targeting this neurotransmitter system might also be useful. We can now test the ability of drugs that target these mechanisms to restore these translational changes seen in ongoing research to develop better treatments for people with 2p16.3 deletion, autism, schizophrenia and Tourette”.
About this genetics and autism research news
Author: Press office
Source: Lancaster University
Contact: Press Office – Lancaster University
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Original research: Access closed.
“Altered activity of the medial prefrontal cortex and dorsal raphe predicts genotype and correlates with abnormal learning behavior in a mouse model of 2p16.3 deletion associated with autism” by Rebecca B. Hughes et al. autism research
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Altered activity of the medial prefrontal cortex and dorsal raphe predicts genotype and correlates with abnormal learning behavior in a mouse model of 2p16.3 deletion associated with autism
2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, significantly increases the risk of developing autism and other neurodevelopmental disorders. We don’t understand how NRXN1 heterozygosity impacts brain function and cognition to increase the risk of developing the disorder.
We characterize here the impact of Nrxn1α heterozygosity on brain metabolism, in mice, using 14C-2-deoxyglucose imaging. We also assess performance in an olfactory discrimination and reverse learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between brain metabolism and Nrxn1α genotype.
Our data show that Nrxn1α heterozygosity induces hypometabolism of the prefrontal cortex (medial prelimbic cortex, mPrL) and contrasting hypermetabolism of the dorsal raphe nucleus (DRN).
Metabolism in these regions allows the predictive classification of Nrxn1α genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1α+/- mouse. behaviorally, Nrxn1α+/- mice show enhanced learning of novel discrimination, impaired reverse learning, and increased latency to make good choices.
Additionally, the male Nrxn1α+/- mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhancement of novel odor discrimination observed in Nrxn1α+/- mice, while DRN hypermetabolism contributes to their increased latency to make the right choices. The data shows that Nrxn1Heterozygosity α impacts the prefrontal cortex and the function of the serotonergic system, which contributes to the cognitive alterations observed in these animals.
The data suggests that Nrxn1α+/- mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion.
