Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits.

Abstract

Creatine (Cr) is a guanidino compound that provides readily available phosphate pools for the regeneration of spent adenosine triphosphate (ATP). The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X-linked SLC6A8 (Creatine transporter; CrT) gene, known as CrT deficiency (CTD). One of the most critical areas that need to be addressed is whether Cr is necessary for brain development. To address this concern, the Slc6a8 gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice using a tamoxifen-inducible Cre recombinase driven by the human ubiquitin C (UBC) promoter. Mice were tested in the Morris water maze, novel, object recognition, and conditioned fear 60 days after Slc6a8 deletion. In addition, overnight locomotor activity was analyzed. Mice that had the gene deleted on P5 showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5 to 10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.