Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene<i>Slc6a8</i>

Udobi, Kenea C.; Kokenge, Amanda N.; Hautman, Emily R.; Ullo, Gabriela; Coene, J.; Williams, Michael T.; Mabondzo, Aloı̈se; Skelton, Matthew R.

doi:10.1101/196063

Cited by 7 publications

(20 citation statements)

References 41 publications

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“…20 Female heterozygous 23 and brain-specific knockouts were hyperactive. 21 While P5KO mice were hyperactive during the dark phase compared with the WT-VEH mice, this was likely due to tamoxifen administration since all mice treated with tamoxifen from P5 to 10 were hyperactive. To our knowledge this is the first study that has shown that neonatal tamoxifen exposure leads to nocturnal hyperactivity.…”

Section: Discussionmentioning

confidence: 95%

“…However, mice with a brain-specific Slc6a8 deletion show visible platform deficits and do not have weight differences. 21 In addition, the P5KO mice do show improvement over trials, suggesting that they are able to perform and learn the task. Finally, the P5KO mice do not show swim speed deficits during the hidden platform trials suggesting that the loss of Cr does not directly impact physical performance.…”

Section: Discussionmentioning

confidence: 99%

“…Novel object recognition (NOR) is a test of incidental learning and memory. 25 Mice were tested in the ANY-box apparatus (Stoelting Company, Wood Dale, Illinois) as previously described in Hautman et al 23 and Udobi et al 21 On the test day, mice were presented with two identical objects and allow to explore until 30 seconds of observation time between objects was accrued. The maximum time for the trial was 10 minutes.…”

Section: Novel Object Recognitionmentioning

confidence: 99%

“…20 Ubiquitous (Slc6a8 −/y ) and brain-specific knockout mice generated from this line have spatial learning, object recognition, and fear memory deficits. 20,21 The purpose of this study was to determine whether the neonatal or adult loss of the Slc6a8 gene was sufficient to cause learning and memory deficits. Using a tamoxifen-inducible CreER T2 , we examined the cognitive effects caused by deletion of the Slc6a8 gene on postnatal day (P)5 or P60.…”

Section: Introductionmentioning

confidence: 99%

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

Udobi

Delcimmuto

Kokenge

et al. 2019

J of Inher Metab Disea

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Creatine (Cr) is a guanidino compound that provides readily available phosphate pools for the regeneration of spent adenosine triphosphate (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‐linked SLC6A8 (Creatine transporter; CrT) gene, known as CrT deficiency (CTD). One of the most critical areas that need to be addressed is whether Cr is necessary for brain development. To address this concern, the Slc6a8 gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice using a tamoxifen‐inducible Cre recombinase driven by the human ubiquitin C (UBC) promoter. Mice were tested in the Morris water maze, novel, object recognition, and conditioned fear 60 days after Slc6a8 deletion. In addition, overnight locomotor activity was analyzed. Mice that had the gene deleted on P5 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 to 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.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Novel Object Recognitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Udobi

Delcimmuto

Kokenge

et al. 2019

J of Inher Metab Disea

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“…We have shown that Slc6a8 -/y and Slc6a8 +/mice have cognitive deficits that are caused by the lack of brain Cr (Skelton et al 2011;Udobi et al 2018). It is important to determine what other behaviors may be disrupted by the lack of Cr.…”

Section: Discussionmentioning

confidence: 99%

Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Abdulla

Pennington

Gutierrez

et al. 2019

Preprint

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Scale; LH: learned helplessness; MAO: monoamine oxidase; PCA: parachloroamphetamine; PCr: phosphocreatine; Slc6a8 -/y : male Slc6a8 knockout mice; Slc6a8 +/y : male wild type mice; Slc6a8 +/-: female mice heterozygous for Slc6a8; Slc6a8 +/+ : female wild type mice; SSRI: selective serotonin reuptake inhibitor; TPH-2: tryptophan hydroxylase-2; TST: tail-suspension test; cLH: rats bred for a congenital LH response Lack of creatine alters serotonin and affect 2 AbstractApproximately 20% of adults in the U.S. will experience an affective disorder during their life. While it is well established that serotonin (5-HT) is a crucial factor in mood, impaired cellular bioenergetics are also implicated. Creatine (Cr), through the Cr/Phospho-Cr (PCr) shuttle, maintains high ATP concentrations in the neuron. This system may be implicated in the etiology of affective disorders, as reduced Cr, PCr, and ATP are often seen in the brains of affected patients. To address this issue, Cr transporter (Crt) deficient male mice (Slc6a8 -/y ) and female mice heterozygous for Crt expression (Slc6a8 +/-) were used to evaluate how a Cr deficient system would alter affective-like behaviors. Slc6a8 -/y and Slc6a8 +/mice had more escapes and faster escape latencies in learned helplessness, indicating a potential resilience to behavioral despair. Elevated zero maze and tail-suspension test performance matched that of wildtype mice, however. Slc6a8 -/y mice have increased 5-hydroxyindoleacetic acid content in the hippocampus and striatum and increased monoamine oxidase protein and tryptophan hydroxylase-2 protein content in the hippocampus, while serotonin levels are unchanged. This indicates an increase in 5-HT turnover. Our results indicate that Cr plays a complex role in affective disorders and 5-HT neurotransmission, warranting further investigation. Lack of creatine alters serotonin and affect 3

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Creatine transport and pathological changes in creatine transporter deficient mice

Wawro

Gajera

Baker

et al. 2021

J of Inher Metab Disea

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The severe impact on brain function and lack of effective therapy for patients with creatine (Cr) transporter deficiency motivated the generation of three ubiquitous Slc6a8 deficient mice (−/y). While each mouse knock-out line has similar behavioral effects at 2 to 3 months of age, other features critical to the efficient use of these mice in drug discovery are unclear or lacking: the concentration of Cr in brain and heart differ widely between mouse lines, there are limited data on histopathologic changes, and no data on Cr uptake. Here, we determined survival, measured endogenous Cr and uptake of its deuteriumlabeled analogue Cr-d3 using a liquid chromatography coupled with tandem mass spectrometry assay, and performed comprehensive histopathologic examination on the Slc6a8 −/y mouse developed by Skelton et al. Our results show that Slc6a8 −/y mice have widely varying organ-specific uptake of Cr-d3, significantly diminished growth with the exception of brain, progressive vacuolar myopathy, and markedly shortened lifespan.

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

Cited by 7 publications

References 41 publications

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

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

Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Creatine transport and pathological changes in creatine transporter deficient mice

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