Deletion of the Creatine Transporter in dopaminergic neurons leads to hyperactivity in mice.

Abstract

Creatine (Cr) is required for proper neuronal function, as evidenced by the intellectual disability and epileptic phenotype seen in patients with cerebral Cr deficiency syndromes (CCDS). In addition, attention-deficit hyperactivity disorder (ADHD) is a frequent co-morbidity of Cr transporter (Crt) deficiency, the leading cause of CCDS. While the effects of the loss of Cr in the whole brain is clear, it is unknown if Cr is required for the proper function of all neurons. Of particular interest are dopaminergic neurons, as many CCDS patients have ADHD and Cr has been implicated in dopamine-associated neurodegenerative disorders, such as Parkinsons and Huntingtons diseases. The purpose of this study was to examine the effect of a loss of the Slc6a8 (Cr transporter; Crt) gene in cells expressing the dopamine transporter (Slc6a3; DAT) on activity levels and motor function as the animals age. DAT-specific Crt-knockout (DAT-Crt) mice were tested along with control (Crt-FLOX) mice monthly from 3 to 12 months of age in locomotor activity, the challenging beam test, and spontaneous activity. DAT-Crt mice were hyperactive compared with controls and this finding persisted throughout the lifetime of the mice. No changes were observed in errors to cross a narrow bridge in the challenging beam test. In a measurement of spontaneous activity, DAT-Crt mice showed increased rearing and hind limb steps, suggesting the hyperactivity carried over to this task. Taken together, these data suggest that the lack of Cr in dopaminergic neurons causes hyperactivity while sparing motor function.\n\nAbbreviations