Human Molecular Genetics Advance Access originally published online on July 19, 2009
Human Molecular Genetics 2009 18(20):3914-3925; doi:10.1093/hmg/ddp334
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Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice
1 Department of Psychiatry and Behavioral Sciences, 2 Dominick P. Purpura Department of Neuroscience and 3 Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA, 4 Brigham and Women's Hospital, Harvard Medical School, New Research Building, Room 250, 77 Avenue Louis Pasteur, Boston, MA 02115, USA, 5 Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA and 6 Division of Pharmacology and Toxicology, Faculty of Pharmacy, PO Box 56 (Viikinkaari 5E), University of Helsinki, Helsinki FIN-00014, Finland
* To whom correspondence should be addressed at: Department of Psychiatry and Behavioral Sciences and Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Golding 104, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Tel: +1 7184303124; Fax: +1 7184303125; Email: hiroi{at}aecom.yu.edu
Received June 15, 2009; Revised July 9, 2009; Accepted July 16, 2009
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 
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 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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.