A mouse model of a patient derived P544L mutation in the Slc6a8 gene shows hypoactivity and cognitive deficits

Creatine (CR) is essential for normal brain function. A lack of brain CR results in intellectual disability, epilepsy, and language delay in humans. The most common cause of CR deficiency in humans results from mutations in the CR transporter (SLC6A8). Several large deletion models of Slc6a8 have been characterized and are excellent models for global creatine loss. However, other SLC6A8 variants are reported in humans with creatine transporter deficiency (CTD), including missense mutations, deletions, and point mutations resulting in phenotypes ranging from mild to severe in humans. The purpose of these experiments was to determine if mice carrying a point mutation of the Slc6a8 gene showed cognitive deficits, further validating a new model of CTD. These Slc6a8 knock-in (Slc6a8^P544L) mice carry the P544L proline to leucine substitution seen in some humans with CTD. The Slc6a8^P544L mice have lower overall body weight and lower brain creatine content. Behavioral assessment revealed deficits in spatial memory but not associative or object recognition memory in Slc6a8^P544L mice. These findings are in line with clinical findings and other CTD models. In addition, we show that Slc6a8^P544L mice are hypoactive in a home-cage environment. These experiments support the use of Slc6a8^P544L mice as a valid representative of behavioral changes in human patients and to develop targeted therapies to rescue specific behavioral deficits in CTD.