Reversal Learning Performance in the XY∗ Mouse Model of Klinefelter and Turner Syndromes

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.

Keywords: Klinefelter syndrome; Turner syndrome; XY∗; animal model; perseveration; reversal learning; sex chromosome aneuploidy.

FIGURE 1

Boxplots of trials to criterion for males (A) and for females (B) grouped by X-dose (number of X-chromosomes; 1X or 2X) and GDX group, and split by the testing phase (Acquisition = ACQ vs. Reversal = REV). Collapsing across and/or splitting by factors in males was based on the omnibus results. Boxes represent median ± quartile, whiskers extend additional 15th of a percentile, gray open circles represent extreme values; black filled circles represent means. Simple effects (p < 0.05) that remained statistically significant after Bonferroni correction are indicated by “^∗”.

FIGURE 2

Boxplots of the difference between the proportion of responses that were correct following either an incorrect response [p(Lose-Shift); index of flexibility] or a correct response [p(Win-Stay); index of stability] for males (A) broken down by gonadectomy group, or for females (B) broken down by X-dose (number of X-chromosomes; 1X or 2X), gonadectomy group and testing phase. Collapsing across and/or splitting by factors was based on the omnibus results. Boxes represent median ± quartile, whiskers extend additional 15th of a percentile, gray open circles represent extreme values; black filled circles represent means. None of the simple effects (p < 0.05) indicated in (B) were significant after Bonferroni correction.

FIGURE 3

Boxplots of maximum consecutive incorrect responses for males (A) and for females (B), as well as the regress score for males (C) broken down by testing phase (Acquisition = ACQ vs. Reversal = REV). Collapsing across and/or splitting by factors was based on the omnibus results. Boxes represent median ± quartile, whiskers extend additional 15th of a percentile, gray open circles represent extreme values; black filled circles represent means. Simple effects (p < 0.05) on either measure that remained statistically significant after Bonferroni correction are indicated by “^∗”. (D) Bivariate scattergram of maximum consecutive incorrect and regress score for males split by group.

FIGURE 4

Top panels are boxplots of log₁₀ of premature responses per trial (+1) split by response side (correct in ACQ vs. correct in REV; C_ACQ vs. C_REV), parsed by testing phase (Acquisition = ACQ vs. Reversal = REV) and Intra-phase Change Point (PRE vs. POST) for males (A) and for females (B). Middle panels are premature responses for males on the C_REV side that are either split by X-dose (number of X-chromosomes; 1X or 2X) and grouped by GDX group (C), or vice versa (D). Bottom panels are premature responses for females on the C_ACQ side that are either split by GDX group and parsed by testing phase and change point (E), or only split by X-dose (F), and premature responses for females on the C_REV side split by GDX group and parsed by testing phase (G). Collapsing across and/or splitting by factors was based on the omnibus results. Simple effects of group (p < 0.05) that remained statistically significant after Bonferroni correction are indicated by “^∗”. Letters “P” and “C” indicate simple effects of Phase and Change Point (p < 0.05), respectively (bold letters indicate significance after Bonferroni correction). Boxes represent median ± quartile, whiskers extend additional 15th of a percentile, gray open circles represent extreme values; black filled circles represent means.

FIGURE 5

Top panels are boxplots of response latencies to target apertures as a function of response side (correct in ACQ = C_ACQ vs. correct in REV = C_REV) for males (A) and for females (B), split by X-dose (number of X-chromosomes; 1X or 2X) or GDX group and parsed by testing phase (Acquisition = ACQ vs. Reversal = REV) and/or Intra-phase Change Point (PRE vs. POST). Middle panels are boxplots of reward-retrieval latencies for males (C) and for females (D) grouped by X-dose, GDX group, testing phase and CP. Bottom panels include box plots of reward retrieval latencies for females collapsed across testing phase and GDX (E) and of trial-initiation latencies for males split by X-dose (F) and for females split by GDX group (G). Collapsing across and/or splitting by factors was guided by the omnibus results. Simple effects of group (p < 0.05) on response latencies and trial initiation latencies that remained statistically significant after Bonferroni correction are indicated by “^∗”. Letters “P” and “C” indicate simple effects of Phase and Change Point (p < 0.05), respectively, on response latencies and trial initiation latencies (bold letters indicate significance after Bonferroni correction). On reward retrieval latencies in males, there was a significant GDX by Phase by Change point interaction (p = 0.048; no significant simple effects, all p > 0.06). On reward retrieval latencies in females, there were main effects of Phase (p = 0.042) and Change Point (p = 0.011), and an X-dose by Change Point interaction (p = 0.033; simple effect of Change Point in 2X, p < 0.0001; all other simple effects, p > 0.12). Boxes represent median ± quartile, whiskers extend additional 15th of a percentile, gray open circles represent extreme values; filled circles represent means.

FIGURE 6

Top panels are boxplots of timeouts/trial due to failures to complete the observing response for males (A) and for females (B), split by X-dose and/or GDX group, and parsed by testing phase (Acquisition = ACQ vs. Reversal = REV) and Intra-phase Change Point (PRE vs. POST). In males, the main effect of Phase was significant (p = 0.0001). Bottom panels are boxplots of extraneous observing responses/trial (i.e., observing responses made during target presentation) for males grouped by GDX group (C) and for females grouped by GDX group or X-dose (D) – both parsed by testing phase. In females, the main effect of Phase was significant (p = 0.00003). Collapsing across and/or splitting by factors was based on the omnibus results. Simple effects (p < 0.05) that remained statistically significant after Bonferroni correction are indicated by “^∗”. Boxes represent median ± quartile, whiskers extend additional 15th of a percentile, gray open circles represent extreme values; black/white circles filled white/black represent means.

FIGURE 7

Boxplots of omissions per trial for males split by X-dose (A) and for females split by X-dose and GDX group (B). Collapsing across and/or splitting by factors was based on the omnibus results. Simple effects (p < 0.05) that remained statistically significant after Bonferroni correction are indicated by “^∗”. Boxes represent median ± quartile, whiskers extend additional 15th of a percentile, gray open circles represent extreme values; black filled circles represent means.