Abstract
Klinefelter syndrome (KS; 47, XXY) and Turner syndrome (TS; 45, XO) are caused by two relatively common sex chromosome aneuploidies. These conditions are associated with an increased odds of neuropsychiatric disorders, including attention deficit/hyperactivity disorder (ADHD), as well as impairments in cognition that include learning delays, attentional dysfunction and impulsivity. We studied cognitive functions in the XY∗ mouse model, which allows comparison of XXY to XY males (KS model), and XO to XX females (TS model). We evaluated adult mice with and without gonads, using a version of an operant reversal-learning task (RLT) that can be used to measure various facets of learning, impulsivity and attention. In the KS model, only one measure related to impulsivity – perseverative responding under reversal conditions – reliably discriminated gonadally intact XXY and XY mice. In contrast, a fundamental learning impairment (more trials to criterion in acquisition phase) in XXY mice, as compared to XY, was observed in gonadectomized subjects. No other task measures showed differences consistent with KS. In the TS mouse model, XO mice did not show a pattern of results consistent with TS, similar to past observations. Thus, the application of this RLT to these XY∗ models reveals only limited behavioral impairments relevant to KS.
Highlights
Trials were first parsed by testing phase and by a derived intra-phase change point (CP) in the learning curve (PRE vs. POST) (Figures 1A,B and Supplementary Figures 1A,B)
Greater perseveration in XXY than XY intact male mice in the reversal-learning task (RLT) is a facet of inflexible responding with face validity for the greater perseverative responding in Klinefelter syndrome (KS) men than controls on the WCST
These results may have implications for the use of androgens to remedy the cognitive deficits observed in KS men
Summary
Sex-chromosome aneuploidies, such as Klinefelter syndrome (KS; 47, XXY) and Turner syndrome (TS; 45, X), are associated with various cognitive impairments and with an increased risk of psychiatric and/or neurodevelopmental disorders, including attention-deficit hyperactivity disorder, autism, schizophrenia, and bipolar disorder (Russell et al, 2006; Cederlöf et al, 2014; Belling et al, 2017; Tartaglia et al, 2017; Zhao and Gong, 2017). To better understand the mechanisms by which sex-chromosome aneuploidies impact phenotypes, various animal models of KS or TS have been developed (Lue et al, 2010; Wistuba, 2010; Cox et al, 2014; Burgoyne and Arnold, 2016). Behavioral studies of these models indicate that both KS and TS aneuploidies impact learning, impulsivity and/or attention (Isles et al, 2004; Davies et al, 2005, 2007; Lue et al, 2005; Lewejohann et al, 2009; Chen et al, 2013b; Cox et al, 2015). In order to better resolve the validity and usefulness of such models, we chose to study an operant spatial reversal-learning task (RLT) using the XY∗ mouse model on a C57BL/6J background, which produces both KS-like and TS-like genotypes and their controls in the same litters
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