Creatine transporter (Slc6a8) knockout mice show an inattentive-like phenotype in the 5-choice serial reaction time test

Abstract

Disorders of creatine (Cr) synthesis and transport cause moderate to severe intellectual disability, epilepsy, and a lack of speech development. Mutations of the X-linked Cr transporter (CrT; SLC6A8) gene are the most frequent cause of Cr deficiency and one of the leading causes of X-linked intellectual disability. There are no treatments for CrT deficiency (CTD) and there are many unanswered questions related to this disorder. Rodent models of CTD have deficits in spatial learning and memory, object recognition memory, fear conditioning, and working memory, making them high-fidelity models of CTD. While these cognitive deficits provide important information related to CTD, they lack some translational relevance and do not address important aspects of executive function like attention and impulsivity. To address this gap in knowledge, we tested brain specific Slc6a8 knockout (bKO) mice in the 5-choice serial reaction time test (5CSRTT), a correlate of the continuous performance task in humans. Following 5CSRTT training, mice were then tested for 3 sessions using trials with a variable stimulus duration followed by 3 sessions using a fixed stimulus duration and variable intertrial interval. During both the testing phases the bKO mice had reduced accuracy along with increased omissions and correct latencies compared with controls. There were no increases in premature responses during the vITI, suggesting that these mice do not have an impulsive phenotype. The results of this study expand the known phenotype of Slc6a8 deficient mice and add a translationally relevant behavioral output to test potential therapies. SynopsisThis study shows that a mouse model of human creatine transporter deficiency, a devastating human condition, has an attention-deficit disorder-like phenotype without an increase in impulsivity.