title: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Go
authors.initials: G
authors.lastname: Suzuki
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Harper
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hiramoto
authors.forename: Birgit
authors.initials: B
authors.lastname: Funke
authors.forename: MoonSook
authors.initials: M
authors.lastname: Lee
authors.forename: Gina
authors.initials: G
authors.lastname: Kang
authors.forename: Mahalah
authors.initials: M
authors.lastname: Buell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Bernice
authors.initials: B
authors.lastname: Morrow
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
authors.forename: Soh
authors.initials: S
authors.lastname: Agatsuma
authors.forename: Noboru
authors.initials: N
authors.lastname: Hiroi
mesh_terms: D000818:Animals; D051186:Armadillo Domain Proteins / Q000235:genetics* / Q000378:metabolism; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D007858:Learning; D008297:Male; D008570:Memory, Short-Term; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C411307:ARVCF protein, human; D051186:Armadillo Domain Proteins; D015815:Cell Adhesion Molecules; D010750:Phosphoproteins; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2; D002394:Catechol O-Methyltransferase