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

Go Suzuki, Kathryn M. Harper, Takeshi Hiramoto, Birgit Funke, Moonsook Lee, Gina Kang, Mahalah Buell, Mark A. Geyer, Raju Kucherlapati, Bernice E. Morrow, Pekka T. Männistö, Soh Agatsuma, Noboru Hiroi

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 ∼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.

Original languageEnglish (US)
Pages (from-to)3914-3925
Number of pages12
JournalHuman Molecular Genetics
Volume18
Issue number20
DOIs
StatePublished - 2009

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Bacterial Artificial Chromosomes
Human Chromosomes
Short-Term Memory
Motivation
Transgenic Mice
Learning
Motor Activity
Phenotype
Enzyme Assays
Interpersonal Relations
Autistic Disorder
Prefrontal Cortex
Intellectual Disability
Cognition
Fear
Hippocampus
Anxiety
Maintenance
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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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. / Suzuki, Go; Harper, Kathryn M.; Hiramoto, Takeshi; Funke, Birgit; Lee, Moonsook; Kang, Gina; Buell, Mahalah; Geyer, Mark A.; Kucherlapati, Raju; Morrow, Bernice E.; Männistö, Pekka T.; Agatsuma, Soh; Hiroi, Noboru.

In: Human Molecular Genetics, Vol. 18, No. 20, 2009, p. 3914-3925.

Research output: Contribution to journalArticle

Suzuki, Go ; Harper, Kathryn M. ; Hiramoto, Takeshi ; Funke, Birgit ; Lee, Moonsook ; Kang, Gina ; Buell, Mahalah ; Geyer, Mark A. ; Kucherlapati, Raju ; Morrow, Bernice E. ; Männistö, Pekka T. ; Agatsuma, Soh ; Hiroi, Noboru. / Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 20. pp. 3914-3925.
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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 ∼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.",
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AU - Suzuki, Go

AU - Harper, Kathryn M.

AU - Hiramoto, Takeshi

AU - Funke, Birgit

AU - Lee, Moonsook

AU - Kang, Gina

AU - Buell, Mahalah

AU - Geyer, Mark A.

AU - Kucherlapati, Raju

AU - Morrow, Bernice E.

AU - Männistö, Pekka T.

AU - Agatsuma, Soh

AU - Hiroi, Noboru

PY - 2009

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N2 - 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.

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