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The Critical Period for Creatine Transporter Deficiency

Udobi, Kenea C
http://orcid.org/0000-0003-4334-6354
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838614741075

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
The discovery of the creatine (Cr)-phosphocreatine (PCr) system has had profound impact on the understanding of cellular bioenergetics, physiology and human pathology. Cr is essential for maintaining ATP homeostasis by providing phosphate pools that can quickly replenish ATP. The importance of Cr is highlighted by individuals with cerebral Cr deficiency syndromes (CCDSs), which are caused by a loss of Cr transport or synthesis. CCDSs are characterized by a wide spectrum of neurological symptoms with intellectual disability, epilepsy, and language impairments being the most frequent. The predominantly neurologic phenotype of CCDS indicates the importance of Cr in proper brain function. Of the mutations that lead to CCDS, Creatine transporter deficiency (CTD) is the most prevalent, affecting 1-2% of males with X-linked intellectual disability (ID). Despite the abundance of Cr in the brain and the striking phenotype of CCDS, little is known about the role Cr plays in brain function. Mouse models have provided invaluable tools for the study of CCDSs. Ubiquitous Slc6a8 knockout mice (Slc6a8-/y) possess a similar phenotype to CTD patients, exhibiting cognitive deficits, and a lack of whole-body Cr but show reductions in size and swim speed that could affect the interpretation of the behavioral data and how subsequent experiments should be designed. To address this, we created brain-specific Slc6a8 knockout (bKO) mice that have reduced cerebral Cr levels and normal Cr levels in peripheral tissue. The bKO mice are similar in stature to wild-type mice and do not show deficits in swim speed. Similar to Slc6a8-/y mice bKO mice have cognitive deficits in the MWM, NOR and CF tasks. This suggests that the Slc6a8-/y mouse is the best model of CTD, as it more closely matches the biochemical phenotype of CTD. To determine the ontogeny of the cognitive and metabolic deficits in CTD, we eliminated the Slc6a8 gene ubiquitously in either adult (postnatal day (P) 60) or neonatal (P5) mice. Both adult and neonatal knockout mice were hyperactive in the open-field test. Elimination of the Slc6a8 gene in adulthood did not result in learning and memory deficits. The P5 knockout mice showed spatial learning deficits evidenced by increases in latency and path length during both phases of the MWM. Neonatal knockout mice also had deficits in object recognition and fear memory. Both groups of mice showed increases in whole-body metabolism and mitochondrial respiration, consistent with Slc6a8-/y mice. The results of this research suggest that cognitive deficits seen in CTD result from changes in the brain due to Cr loss during early brain development.
Charles Vorhees, Ph.D (Committee Chair)
Zaza A. Khuchua, Ph.D (Committee Member)
Steve Danzer, Ph.D. (Committee Member)
Christina Gross, Ph.D. (Committee Member)
Taosheng Huang, Ph.D.,M.D. (Committee Member)
Matthew Skelton, Ph.D. (Committee Member)
165 p.
Neurology
creatine; cellular metabolism; mitochondria; intellectual disability; creatine transporter

Recommended Citations

Citations

  • Udobi, K. C. (2018). The Critical Period for Creatine Transporter Deficiency [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838614741075

    APA Style (7th edition)

  • Udobi, Kenea. The Critical Period for Creatine Transporter Deficiency. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838614741075.

    MLA Style (8th edition)

  • Udobi, Kenea. "The Critical Period for Creatine Transporter Deficiency." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838614741075

    Chicago Manual of Style (17th edition)

ucin1543838614741075
228
© 2018, some rights reserved.Creative Commons License The Critical Period for Creatine Transporter Deficiency by Kenea C Udobi is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.