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

Abstract

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, using 14 C-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 Nrxn1α +/À mice. Behaviorally, Nrxn1α +/À mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1α +/À mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1α +/À mice, 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 Nrxn1α +/À mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. Lay SummaryDeletion 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.

16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability

“…However, enhanced cognitive performance is detected in other mouse models of ASD with high construct validity. For example, enhanced learning is seen in various mouse models with ASD-related mutations, including Shank1 −/− 107 , Taok2 −/− 108 , Ctnbb1 −/– (Pvalb cell conditional) 109 , Nrxn1α +/− mice 110 and also in Aspm −/− mice that show reduced TRN Pvalb expression 111 . A recent publication reports that mice with an ASD-associated neuroligin-3 mutation also show enhanced ability in the rCPT 112 .…”

Enhanced fear limits behavioral flexibility in Shank2-deficient mice

“…These results are consistent with our finding that Shank2-KO mice were intact in reversal learning when only appetitive outcomes were used. However, numerous other studies found that reversal learning was impaired in various ASD model mice in the absence of an aversive outcome [16][17][18][19][20][22][23][24][25][26][27][28][29]. It is difficult to compare findings across studies because the studied genotypes and experimental procedures have varied widely.…”

“…People with ASD also show impairments in reversal learning, and their performance in reversal learning correlates with clinical ratings of restricted and repetitive behavior [14] and everyday symptoms of behavioral inflexibility [15]. Impaired behavioral flexibility has also been reported in mouse models of ASD [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Thus, a growing body of studies indicates that impaired behavioral flexibility is present and correlated with repetitive and restrictive behaviors in ASD, raising the possibility that repetitive and restrictive patterns of behavior associated with ASD might be manifestations of impaired flexibility.…”

Copy Number Variations in Neuropsychiatric Disorders

“…According to previous research [ 126 ], alterations in serotonin system function and the medial prefrontal cortex (PFC), as a result of 2p16.3 ( NRXN1 ), may contribute to some of the behavioral alterations; therefore, CNV increases the risk of developing neurodevelopmental disorders. They found, in mice, that reduced Nrxn1α expression induces prefrontal cortex hypometabolism and impairs cognitive flexibility.…”