Connectomic and behavioral alterations in creatine transporter deficiency are partially normalized by gene therapy

Abstract

AbstractCreatine Transporter Deficiency (CTD) is an X-linked disease due to the loss ofSLC6A8gene and presenting with low brain creatine, intellectual disability, autistic-like behavior and seizures. No treatments are available yet for CTD, and little is known about the brain circuit alterations underlying its pathological endophenotypes. Here, we tracked brain network and behavioral dysfunction in a murine model of CTD at two stages of disease progression. fMRI mapping revealed widespread disruption of brain connectivity in Slc6a8-KO mutants, with prominent somato-motor dysconnectivity in juvenile mice, and weaker and more focal cortical and subcortical hypoconnectivity in adults. Notably, perinatal AAV-mediated expression of humanSLC6A8in Slc6a8-KO mutants significantly rescued juvenile fMRI hypoconnectivity. This effect was paralleled by a regression of translationally relevant phenotypes, including a reduction in stereotyped movements and increased body weight which persisted into adulthood. Cognitive deficits and residual fMRI hypoconnectivity in adult mice were instead not reverted by gene therapy. Finally, multivariate modeling in adult mice revealed a basal forebrain network whose activity was associated with behavioral performance, and modulated by brain creatine levels. This brain-behavior relationship was disrupted in Slc6a8-KO mutants. Our results document robust network disruption in CTD and demonstrate that CTD pathology can be partially reversed by perinatal genetic expression ofSLC6A8, thus laying the basis for the development of experimental therapies for this genetic disorder.