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Copy number variants, such as duplications and hemizygous deletions at chromosomal loci of up to a few million base pairs, are highly associated with psychiatric disorders. Hemizygous deletions at human chromosome 22q11.2 were found to be associated with elevated instances of schizophrenia and autism spectrum disorder in 1992 and 2002, respectively. Following these discoveries, many mouse models have been developed and tested to analyze the effects of gene dose alterations in small chromosomal segments and single genes of 22q11.2. Despite several limitations to modeling mental illness in mice, mouse models have identified several genes on 22q11.2—Tbx1, Dgcr8, Comt, Sept5, and Prodh—that contribute to dimensions of autism spectrum disorder and schizophrenia, including working memory, social communication and interaction, and sensorimotor gating. Mouse studies have identified that heterozygous deletion of Tbx1 results in defective social communication during the neonatal period and social interaction deficits during adolescence/adulthood. Overexpression of Tbx1 or Comt in adult neural progenitor cells in the hippocampus delays the developmental maturation of working memory capacity. Collectively, mouse models of variants of these 4 genes have revealed several potential neuronal mechanisms underlying various aspects of psychiatric disorders, including adult neurogenesis, microRNA processing, catecholamine metabolism, and synaptic transmission. The validity of the mouse data would be ultimately tested when therapies or drugs based on such potential mechanisms are applied to humans.

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.

Multiple genes are thought to influence both susceptibility to nicotine dependence and its comorbid behavioral traits in humans. However, which specific genes contribute to this pleiotropic effect is poorly understood. Previous rodent studies have shown that many addictive substances and stressful stimuli increase the expression of the transcription factor FosB in limbic and associated regions and that the protein products of fosB contribute to certain behavioral effects of cocaine and morphine. However, the role of this gene in nicotine-regulated behaviors and dependence-related behavioral traits is unknown. We tested the hypothesis that a constitutive level of FosB affects nicotine-regulated behaviors and comorbid behavioral traits using constitutive fosB knockout (KO) mice. Following repeated or prolonged nicotine administration, but not a single acute administration, KO mice were impaired in conditioned place preference, oral nicotine intake and motor suppression. In wild-type mice, repeated nicotine injections, but not a single acute injection, increased the expression of FosB and its truncated variant DeltaFosB in the targets but not at the origins of the mesolimbic and nigrostriatal dopamine pathways; no detectable level of FosB/DeltaFosB was found in KO mice. In tasks designed to assess behavioral traits, KO mice exhibited more pronounced behavioral abnormalities when stress levels were high than when they were minimized. Our results suggest that the constitutive absence of fosB has a pleiotropic influence on the behavioral effects of repeated or prolonged nicotine administration and on stress-related behavioral traits in mice.