TY - JOUR T1 - Normal performance of <em>Fmr1</em> mice on a touchscreen delayed non-matching to position working memory task JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0143-15.2016 SP - ENEURO.0143-15.2016 AU - Prescott T. Leach AU - Jane Hayes AU - Michael Pride AU - Jill L. Silverman AU - Jacqueline N. Crawley Y1 - 2016/02/24 UR - http://www.eneuro.org/content/early/2016/02/24/ENEURO.0143-15.2016.abstract N2 - Fragile X syndrome is a neurodevelopmental disorder characterized by mild to severe cognitive deficits. The complete absence of Fmr1 and its protein product in the mouse model of Fragile X (Fmr1 KO) provides construct validity. A major conundrum in the field is the remarkably normal performance of Fmr1 mice on cognitive tests in most reports. One explanation may be insufficiently challenging cognitive testing procedures. Here we developed a delayed non-matching to position touchscreen task to test the hypothesis that paradigms placing demands on working memory would reveal robust and replicable cognitive deficits in the Fmr1 KO mouse. We first tested Fmr1 KO mice (Fmr1) and their wildtype littermates (WT) in a simple visual discrimination task, followed by assessment of reversal learning. We then tested Fmr1 and WTs in a new touchscreen non-match to position task and subsequently challenged their working memory abilities by adding delays, representing a higher cognitive load. Performance by Fmr1 KO was equal to WTs on both touchscreen tasks. Lastly, we replicated previous reports of normal performance by Fmr1 on Morris water maze spatial navigation and reversal. These results indicate that, while the Fmr1 mouse model effectively recapitulates many molecular and cellular aspects of Fragile X syndrome, the cognitive profile of Fmr1 mice generally does not recapitulate the primary cognitive deficits in the human syndrome, even when diverse and challenging tasks are imposed.Significance Statement: Traditional cognitive tests have revealed surprisingly normal performance in the Fmr1 knockout mouse model (Fmr1) of Fragile X syndrome (FXS). Here we introduce novel methods for conducting working memory tasks, following discrimination and reversal learning tasks, to interrogate Fmr1 mice with a diverse set of cognitive challenges. Touchscreen technology, incorporating direct analogies to methods used to evaluate cognitive abilities in human subjects and non-human primates, was employed to evaluate Fmr1 mice on simple pairwise discrimination, reversal, non-matching to position, and delayed non-matching to position. No significant deficits were detected in Fmr1 mice, supporting the interpretation that this widely-used mouse model of FXS is not optimal for discovering pharmacological therapeutics that improve cognitive functioning in individuals with FXS. ER -