scholarly journals Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits

2019 ◽  
Vol 42 (5) ◽  
pp. 966-974 ◽  
Author(s):  
Kenea C. Udobi ◽  
Nicholas Delcimmuto ◽  
Amanda N. Kokenge ◽  
Zuhair I. Abdulla ◽  
Marla K. Perna ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Transporter Gene ◽  
Creatine Transporter ◽  
Adult Mice

scholarly journals Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8

2017 ◽  
Author(s):  
Kenea C. Udobi ◽  
Amanda N. Kokenge ◽  
Emily R. Hautman ◽  
Gabriela Ullo ◽  
Julie Coene ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Water Maze ◽  
Memory Deficits ◽  
Whole Body ◽  
Novel Object Recognition ◽  
Transporter Gene ◽  
Biochemical Phenotype ◽  
Creatine Transporter ◽  
Novel Object ◽  
Path Lengths

AbstractCreatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language, and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8flox) mice to create ubiquitous Slc6a8 knockout (Slc6a8-/y) mice. Slc6a8-/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8-/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8Flox mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8-/y mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8-/ymice. The results demonstrate that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8-/y mice.

scholarly journals Deletion of the creatine transporter gene in neonatal, but not adult, mice lead to cognitive deficits

2019 ◽  
Author(s):  
Kenea C. Udobi ◽  
Nicholas Delcimmuto ◽  
Amanda N. Kokenge ◽  
Zuhair I. Abdulla ◽  
Marla K. Perna ◽  
...  
Keyword(s):  
Brain Development ◽  
Cognitive Deficits ◽  
Knockout Mice ◽  
Language Impairment ◽  
Dark Phase ◽  
Creatine Transporter ◽  
Adult Mice ◽  
Object Learning ◽  
Critical Areas ◽  
Severe Intellectual Disability

AbstractCreatine (Cr) is a guanidino compound that provides readily-available phosphate pools for the regeneration of spent ATP. The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X-linkedSLC6A8(Creatine transporter; CrT) gene, known as CrT deficiency (CTD). There are no current treatments for CTD and the mechanisms that underlie the cognitive deficits are poorly understood. One of the most critical areas that need to be addressed is if Cr is necessary for brain development. To address this concern, theSlc6a8gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice. The P5 knockout mice showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5-10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.Take-home messageThe learning and memory deficits seen in Slc6a8-deficient mice are likely due to the developmental loss of Cr.

scholarly journals X-Linked Mental Retardation with Seizures and Carrier Manifestations Is Caused by a Mutation in the Creatine-Transporter Gene (SLC6A8) Located in Xq28

2002 ◽  
Vol 70 (5) ◽  
pp. 1349-1356 ◽  
Author(s):  
Kimberly A. Hahn ◽  
Gajja S. Salomons ◽  
Darci Tackels-Horne ◽  
Tim C. Wood ◽  
Harold A. Taylor ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Transporter Gene ◽  
Creatine Transporter

scholarly journals Cyclocreatine treatment ameliorates the cognitive, autistic and epileptic phenotype in a mouse model of Creatine Transporter Deficiency

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesco Cacciante ◽  
Mariangela Gennaro ◽  
Giulia Sagona ◽  
Raffaele Mazziotti ◽  
Leonardo Lupori ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Benefit ◽  
Behavioral Disturbances ◽  
Creatine Transporter ◽  
Chemically Modified ◽  
Eeg Abnormalities ◽  
Creatine Transporter Deficiency ◽  
Novel Biomarkers ◽  
Transporter Deficiency ◽  
Potential Therapeutic Benefit

Abstract Creatine Transporter Deficiency (CTD) is an inborn error of metabolism presenting with intellectual disability, behavioral disturbances and epilepsy. There is currently no cure for this disorder. Here, we employed novel biomarkers for monitoring brain function, together with well-established behavioral readouts for CTD mice, to longitudinally study the therapeutic efficacy of cyclocreatine (cCr) at the preclinical level. Our results show that cCr treatment is able to partially correct hemodynamic responses and EEG abnormalities, improve cognitive deficits, revert autistic-like behaviors and protect against seizures. This study provides encouraging data to support the potential therapeutic benefit of cyclocreatine or other chemically modified lipophilic analogs of Cr.

Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application

2007 ◽  
Vol 28 (9) ◽  
pp. 890-896 ◽  
Author(s):  
Efraim H. Rosenberg ◽  
Cristina Martínez Muñoz ◽  
Ofir T. Betsalel ◽  
Silvy J.M. van Dooren ◽  
Matilde Fernandez ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Transporter Gene ◽  
Creatine Transporter ◽  
Diagnostic Application ◽  
Missense Variants

Skeletal Muscle Total Creatine Content and Creatine Transporter Gene Expression in Vegetarians Prior to and Following Creatine Supplementation

2004 ◽  
Vol 14 (5) ◽  
pp. 517-531 ◽  
Author(s):  
Kenneth K.O. Watt ◽  
Andrew P. Garnham ◽  
Rodney J. Snow
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Alternative Treatment ◽  
Creatine Supplementation ◽  
Crossover Design ◽  
Transporter Gene ◽  
Double Blind ◽  
Creatine Transporter ◽  
Before And After ◽  
Total Creatine

This study examined the effect of vegetarianism on skeletal muscle total creatine (TCr) content and creatine transporter (CreaT) gene expression, prior to and during 5 d of Cr supplementation (CrS). In a double-blind, crossover design, 7 vegetarians (VEG) and nonvegetarians (NVEG) were assigned Cr or placebo supplements for 5 d and after 5 wk, received the alternative treatment. Muscle sampling occurred before, and after 1 and 5 d of treatment ingestion. Basal muscle TCr content was lower (P < 0.05) in VEG compared with NVEG. Muscle TCr increased (P < 0.05) throughout the Cr trial in both groups but was greater (P < 0.05) in VEG compared with NVEG, at days 1 and 5. CreaT gene expression was not different between VEG and NVEG. The results indicate that VEG have a lower muscle TCr content and an increased capacity to load Cr into muscle following CrS. Muscle CreaT gene expression does not appear to be affected by vegetarianism.

scholarly journals Sustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in mice

2021 ◽  
pp. 026988112110085
Author(s):  
Sara R Tanqueiro ◽  
Francisco M Mouro ◽  
Catarina B Ferreira ◽  
Céline F Freitas ◽  
João Fonseca-Gomes ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Receptor Expression ◽  
Facilitatory Effect ◽  
Impaired Performance ◽  
Adult Mice ◽  
Tropomyosin Related Kinase B ◽  
Neurotropic Factor ◽  
And Function

Background: Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown. Aims: The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction. Methods: Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis. Results: The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP. Conclusions: Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.

scholarly journals Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter geneSlc6a8

2018 ◽  
Vol 17 (6) ◽  
pp. e12461 ◽  
Author(s):  
K. C. Udobi ◽  
A. N. Kokenge ◽  
E. R. Hautman ◽  
G. Ullio ◽  
J. Coene ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Creatine Transporter
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