Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion.

Scientists studied mice with a genetic change similar to one found in some people with autism. They found these mice had different brain activity patterns - less activity in the thinking part of the brain and more in the mood-related area. The mice were good at learning new things but struggled when rules changed, which is similar to challenges some autistic people face with flexible thinking.

This preclinical study examined mice with Nrxn1α heterozygosity, modeling the 2p16.3 chromosomal deletion associated with increased autism risk. Researchers used glucose imaging to assess brain metabolism and tested mice on olfactory discrimination and reversal learning tasks. Results showed that Nrxn1α heterozygous mice displayed prefrontal cortex hypometabolism and dorsal raphé nucleus hypermetabolism, with these brain metabolic patterns predicting genotype. Behaviorally, these mice demonstrated enhanced novel discrimination learning but impaired reversal learning (cognitive flexibility) and increased decision latency.

Male mice also showed hyperlocomotor activity. Correlative analyses suggested that prefrontal cortex changes contributed to enhanced discrimination while dorsal raphé changes related to delayed decision-making.

Provides insights into how 2p16.3 deletion may contribute to autism risk through prefrontal cortex dysfunction. Suggests this mouse model could be useful for testing interventions targeting cognitive flexibility deficits in autism-related neurodevelopmental conditions.

Animal model study with unclear sample sizes. Findings may not directly translate to humans. Limited to one specific genetic variant. Correlative rather than causal relationships between brain metabolism and behavior.

2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1α heterozygosity on cerebral metabolism, in mice, usingC-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity.

We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1α genotype. Our data show that Nrxn1α heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1α genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1αmice.

Behaviorally, Nrxn1αmice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1αmice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1αmice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1α heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals.

The data suggest that Nrxn1αmice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. LAY SUMMARY: Deletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1α expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex.

Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism.