Casp2-/- mice are protected from cognitive symptoms of HD in the YAC128 mouse. A) Mice were trained in a swimming T-maze to find a submerged platform in one arm of the maze. Acquisition time of the platform location does not differ between genotypes during the first 12 trials (two-way repeated measures ANOVA genotype: F(3,638) = 0.56, p = 0.64). Before trial 1 of the reversal phase on day 5, the platform was switched to the opposite arm of the T-maze. Time to the platform in its new location differed by genotype across the 4 trials (two-way repeated measures ANOVA, genotype: F(3,147) = 2.90, p = 0.043). YAC128 mice take significantly longer to reach the platform on the first trial than Casp2-/-;YAC128 mice (19.5 seconds vs. 10.86 seconds, Bonferroni t = 3.205, p < 0.01). Data represent mean +/- SEM. N = 33 WT mice, 28 YAC128 mice, 28 casp2-/- mice and 24 Casp2-/-;YAC128 mice. B) Increased time to platform in the YAC128 mice was primarily due to increased perseveration during the first trial. YAC128 mice re-entered the previously correct arm more frequently than Casp2-/-;YAC128 mice (two-way repeated measures ANOVA Trial F(3,174) = 10.19, p < 0.0001; YAC128 F(3,174) = 2.04, p = 0.12; Interaction F(9,174) = 1.42, p = 0.18; Bonferroni post-hoc test significance indicated). N = 21 WT mice, 28 YAC128 mice, 17 casp2-/- mice and 24 Casp2-/-;YAC128 mice. C) YAC128;casp2-/- are rescued from deficits in a T-maze spontaneous alternation task. 7-month old Mice were exposed to a T-maze with a divider forcing them to choose one arm, which they were restrained to for 1 minute. After this familiarization trial, the mice re-entered the T-maze and their arm choice recorded. WT mice prefer the novel arm of the maze 79% of the time, while YAC128 mice only choose the novel arm 53% of the time. Casp2-/- and YAC128;casp2-/- choose the novel arm 77% and 73% of the time, similar to WT mice. N = 15 WT mice, 21 YAC128 mice, 17 casp2-/- mice and 15 Casp2-/-;YAC128 mice.