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Evaluating a lack of creatine in the monoaminergic neurotransmitter system

Abdulla, Zuhair I
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573225385280837

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
The creatine (Cr)/phosphoCr (PCr) shuttle acts as an ATP buffer for cells with a high energy demand. This shuttle uses Cr kinases to catalyze the conversion of ADP to ATP using the phosphate group from PCr. Cr’s buffering capacity decreases reliance on slow energy generating processes by maintaining ATP levels. Its importance to neurological function is made clear by cerebral creatine deficiency syndromes (CCDS), disorders caused by an absence of Cr. The primary symptoms of CCDS are neurological, the most prominent being intellectual disability (ID). Cr transporter (Crt) deficiency (CTD) is the most common CCDS, itself accountable for ~2% of all X-linked ID. CTD is caused by mutations in SLC6A8, rendering the Crt dysfunctional, resulting in an absence of brain Cr. Approximately 50% of patients also have attentional deficits and/or hyperactivity and motoric impairments are also observed. It is unknown how the lack of cellular Cr causes this disorder. Crt knockout mice (Slc6a8-/y) have cognitive deficits, lack brain Cr, and are a high-fidelity model of CTD. Slc6a8-/y mice have spatial learning and memory, object recognition, and fear memory deficits. Aside from the phenotype of CCDSs, little else is known about brain Cr function. This dissertation aims to further characterize the behavioral effects of Cr deficiency. Decreased brain Cr concentrations are observed in several psychiatric disorders, including depression, schizophrenia, and anxiety. In rats and mice, Cr increased coping behaviors in the forced-swim test and the tail-suspension test (TST). As an adjunct to serotonergic antidepressants in humans, Cr improves depressive symptoms faster and to a greater degree than antidepressants alone. Relatedly, Slc6a8-/y mice have increased 5-hydroxyindoleacetic acid and serotonin (5-HT), indicating an abnormal serotonergic system. These data suggest that Slc6a8-/y mice would have an altered affective phenotype. Slc6a8-/y and female mice heterozygous for Slc6a8 mutation (Slc6a8+/-) were tested in elevated zero maze (EZM), TST, and learned helplessness. EZM and TST performance did not differ from wild type controls, but Slc6a8-/y and Slc6a8+/- mice were resilient to learned helplessness, indicating that Cr may be important in induced-depressive like behaviors. Brain Cr reductions are also common in motor disorders tied to dopaminergic impairment. Cr protects against toxins used to model motor impairments in rodents. To assess Cr’s role in motor activity, we created mice lacking Crt in dopamine neurons (dCrt-/y). Motor ability was assessed monthly from postnatal day (P) 90 until P360 in dCrt-/y mice using the challenging beam, spontaneous activity, and overnight locomotor assays. While no motor deficits emerged, dCrt-/y mice are persistently hyperactive. Finally, it is unknown why Cr deficiencies cause cognitive deficits. Slc6a8-/y mice have serotonergic abnormalities, and 5-HT is involved in cognition. Serotonergic drugs (i.e. MDMA and citalopram) causes lasting cognitive deficits in developing rats. Serotonergic antidepressants improve cognition in individuals with depression. Therefore, we hypothesized that mice lacking Crt in serotonergic neurons (sCrt-/y) would have the same cognitive deficits as Slc6a8-/y mice. Morris water maze, novel object recognition, and conditioned fear testing indicated that the 5-HT system does not contribute to the learning and memory deficits of Slc6a8-/y mice.
Christina Gross, Ph.D. (Committee Chair)
Gary Gudelsky, Ph.D. (Committee Member)
Kim Seroogy, Ph.D. (Committee Member)
Matthew Skelton, Ph.D. (Committee Member)
Michael Williams, Ph.D. (Committee Member)
167 p.
Neurology
Creatine; Monomamines; Dopamine; Serotonin; Affect; energy

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Citations

  • Abdulla, Z. I. (2019). Evaluating a lack of creatine in the monoaminergic neurotransmitter system [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573225385280837

    APA Style (7th edition)

  • Abdulla, Zuhair. Evaluating a lack of creatine in the monoaminergic neurotransmitter system. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573225385280837.

    MLA Style (8th edition)

  • Abdulla, Zuhair. "Evaluating a lack of creatine in the monoaminergic neurotransmitter system." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573225385280837

    Chicago Manual of Style (17th edition)

ucin1573225385280837
372
© 2019, some rights reserved.Creative Commons License Evaluating a lack of creatine in the monoaminergic neurotransmitter system by Zuhair I Abdulla 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.