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Deletion of the Creatine Transporter (Slc6a8) in Dopaminergic Neurons Leads to Hyperactivity in Mice

  • Zuhair I. Abdulla
  • Bahar Pahlevani
  • Kerstin H. Lundgren
  • Jordan L. Pennington
  • Kenea C. Udobi
  • Kim B. Seroogy
  • Matthew R. SkeltonEmail author
Article
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Abstract

The lack of cerebral creatine (Cr) causes intellectual disability and epilepsy. In addition, a significant portion of individuals with Cr transporter (Crt) deficiency (CTD), the leading cause of cerebral Cr deficiency syndromes (CCDS), are diagnosed with attention-deficit hyperactivity disorder. While the neurological effects of CTD are clear, the mechanisms that underlie these deficits are unknown. Part of this is due to the heterogenous nature of the brain and the unique metabolic demands of specific neuronal systems. Of particular interest related to Cr physiology are dopaminergic neurons, as many CCDS patients have ADHD and Cr has been implicated in dopamine-associated neurodegenerative disorders, such as Parkinson’s and Huntington’s diseases. The purpose of this study was to examine the effect of a loss of the Slc6a8 (Crt) gene in dopamine transporter (Slc6a3; DAT) expressing cells on locomotor activity and motor function as the mice age. Floxed Slc6a8 (Slc6a8flox) mice were mated to DATIREScre expressing mice to generate DAT-specific Slc6a8 knockouts (dCrt−/y). Locomotor activity, spontaneous activity, and performance in the challenging beam test were evaluated monthly in dCrt−/y and control (Slc6a8flox) mice from 3 to 12 months of age. dCrt−/y mice were hyperactive compared with controls throughout testing. In addition, dCrt−/y mice showed increased rearing and hindlimb steps in the spontaneous activity test. Latency to cross the narrow bridge was increased in dCrt−/y mice while foot slips were unchanged. Taken together, these data suggest that the lack of Cr in dopaminergic neurons causes hyperactivity while sparing motor function.

Keywords

Creatine Creatine transporter DAT-Cre Hyperactivity Motor function 

Notes

Acknowledgments

The authors would like to thank Marla K. Perna and Keila N. Miles for providing scientific input and proofreading this article.

Author Contributions

Mr. Abdulla, Dr. Seroogy, and Dr. Skelton designed the experiment and drafted and edited the manuscript. Mr. Abdulla, Ms. Pahlevani, Ms. Lundgren, Ms. Pennington, and Mr. Udobi conducted and scored all experiments.

Funding Information

This work was supported by National Institutes of Health grant HD080910 and a CARE grant from the Association of Creatine Deficiencies. Portions were supported by the Kerman Family Fund, the Selma Schottenstein Harris Lab for Research in Parkinson’s, the Gardner Family Center for Parkinson’s Disease and Movement Disorders, and the Parkinson’s Disease Support Network, Ohio, Kentucky, and Indiana.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PediatricsUniversity of Cincinnati College of Medicine and Division of Neurology, Cincinnati Children’s Research FoundationCincinnatiUSA
  2. 2.Department of Neurology, College of MedicineUniversity of CincinnatiCincinnatiUSA
  3. 3.Neuroscience Graduate ProgramUniversity of CincinnatiCincinnatiUSA

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