Mutations in the creatine transporter gene (Slc6a8) lead to the inability to transport Cr from the blood into the brain. Children carrying a mutant CrT gene develop progressive intellectual impairment, loss of speech, behavioral abnormalities, and often epilepsy.

To date, no model of CrT deficiency exists, even though this newly discovered illness is thought to affect 2 percent to 3 percent of all X-linked cases of mental retardation. We created mice with exons 2-4 of Slc6a8 flanked by loxP sites and crossed these to CreCMV mice to create a line of CrT knockout mice with the CrT protein inactive in all tissues, as occurs in humans. Because CrT is X-linked, only males express the disorder.

This is also the case in the mutant mice. CrT-/y (affected) mice lack Cr in the brain and muscle with significant reductions in other tissues, including the heart and testes. CrT-/y mice show impaired spatial learning in the Morris water maze and impaired reference memory for where the platform used to be after it is removed. CrT-/y mice also show impaired preference for new objects over ones previously seen, unlike normal mice (or people). In another test, affected mice also fail to show normal conditioning to a tone associated with an aversive stimulus. Finally, CrT-/y mice have increased serotonin in the hippocampus and prefrontal cortex, areas critical for learning and memory.

Thus far, the knockout mice show signs that converge with those seen in affected children, offering the potential to use this mouse model to understand what creatine does in neurons, and for developing treatments for getting Cr into the brain in the absence of the transporter protein.