Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice

Abstract

Duplication of human chromosome 22q11.2 is associated with elevated rates of mental retardation, autism and many other behavioral phenotypes. However, because duplications cover 1.5-6 Mb, the precise manner in which segments of 22q11.2 causally affect behavior is not known in humans. We have now determined the developmental impact of over-expression of an approximately 190 kb segment of human 22q11.2, which includes the genes TXNRD2, COMT and ARVCF, on behaviors in bacterial artificial chromosome (BAC) transgenic (TG) mice. BAC TG mice and wild-type (WT) mice were tested for their cognitive capacities, affect- and stress-related behaviors and motor activity at 1 and 2 months of age. An enzymatic assay determined the impact of BAC over-expression on the activity level of COMT. BAC TG mice approached a rewarded goal faster (i.e. incentive learning), but were impaired in delayed rewarded alternation during development. In contrast, BAC TG and WT mice were indistinguishable in rewarded alternation without delays, spontaneous alternation, prepulse inhibition, social interaction, anxiety-, stress- and fear-related behaviors and motor activity. Compared with WT mice, BAC TG mice had an approximately 2-fold higher level of COMT activity in the prefrontal cortex, striatum and hippocampus. These data suggest that over-expression of this 22q11.2 segment enhances incentive learning and impairs the prolonged maintenance of working memory, but has no apparent effect on working memory per se, affect- and stress-related behaviors or motor capacity. High copy numbers of this 22q11.2 segment might contribute to a highly selective set of phenotypes in learning and cognition during development.

A rare case of trisomy 11q23.3-11q25 and trisomy 22q11.1-22q11.21

“…Duplication of chromosome 22q11.2 is associated with elevated rates of mental retardation, autism, and other behavioral phenotypes, and probably includes abnormalities in several key genes such as TXNRD2, COMT, ARVCF, and TBX1. TXNRD2 is a thioredoxin reductase that directly reduces proteins (Gasdaska et al, 1999); COMT is one of the most extensively studied 22q11.2 genes related to cognitive function (Rosa et al, 2004) and ARVCF may contribute to the phenotype of VCFS (Suzuki et al, 2009). Moreover, TBX1 has been shown to be the major genetic component responsible for the features of DGS/VCFS.…”

Common Genetic Variants and Risk of Brain Injury After Preterm Birth

“…with schizophrenia 36,37,41,42 ; overexpression of the region in mice leads to alterations in incentive learning and working memory 43 ; common variants in ARVCF are associated with an intermediate MRI phenotype that includes altered FA in patients who have schizophrenia 44 ; and SNPs in COMT are associated with white matter changes in preterm-born adults. 45 The association between a tag SNP in ARVCF and reduced FA in white matter after preterm birth could be explained by: common variation at ARVCF influencing white matter microstructure, which has been reported in adult-onset schizophrenia 44 ; the SNP being in strong linkage disequilibrium (LD) with nongenotyped SNPs that span COMT (Supplementary Fig 1A); or a regulatory role on gene expression.…”

Mouse Models of 22q11.2-Associated Autism Spectrum Disorder

“…As a pair of mice is placed in a cage that is novel to both, there is no ‘resident’ mouse in this task; aggressive social interaction is minimized and affiliative social interaction is maximally evaluated [93,108]. Unlike a “sociability” task in which one of the mice is confined in a small wire cage, reciprocal interaction can be evaluated in this naturalistic social interaction task [111].…”