Evaluating a lack of creatine in the monoaminergic neurotransmitter system

Evaluating a lack of creatine in the monoaminergic neurotransmitter system

Bibliographic Details
Main Author: Abdulla, Zuhair I.
Language:English
Published: University of Cincinnati / OhioLINK 2019
Subjects:
Neurology
Creatine
Monomamines
Dopamine
Serotonin
Affect
energy
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573225385280837
id ndltd-OhioLink-oai-etd.ohiolink.edu-ucin1573225385280837
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Neurology
Creatine
Monomamines
Dopamine
Serotonin
Affect
energy
spellingShingle Neurology
Creatine
Monomamines
Dopamine
Serotonin
Affect
energy
Abdulla, Zuhair I.
Evaluating a lack of creatine in the monoaminergic neurotransmitter system
author Abdulla, Zuhair I.
author_facet Abdulla, Zuhair I.
author_sort Abdulla, Zuhair I.
title Evaluating a lack of creatine in the monoaminergic neurotransmitter system
title_short Evaluating a lack of creatine in the monoaminergic neurotransmitter system
title_full Evaluating a lack of creatine in the monoaminergic neurotransmitter system
title_fullStr Evaluating a lack of creatine in the monoaminergic neurotransmitter system
title_full_unstemmed Evaluating a lack of creatine in the monoaminergic neurotransmitter system
title_sort evaluating a lack of creatine in the monoaminergic neurotransmitter system
publisher University of Cincinnati / OhioLINK
publishDate 2019
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573225385280837
work_keys_str_mv AT abdullazuhairi evaluatingalackofcreatineinthemonoaminergicneurotransmittersystem
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin15732253852808372021-08-03T07:13:05Z Evaluating a lack of creatine in the monoaminergic neurotransmitter system Abdulla, Zuhair I. Neurology Creatine Monomamines Dopamine Serotonin Affect energy 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. 2019 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573225385280837 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573225385280837 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.

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