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Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency.

Skelton MR, Schaefer TL, Graham DL, Degrauw TJ, Clark JF, Williams MT, Vorhees CV - PLoS ONE (2011)

Bottom Line: Male CrT(⁻/y) (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes.CrT(⁻/y) mice showed increased path length during acquisition and reversal learning in the Morris water maze.Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Cincinnati Children's Research Foundation, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America. Matthew.skelton@cchmc.org

ABSTRACT
Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2-4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT(⁻/y) (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT(⁻/y) mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT(⁻/y) mice showed increased average distance from the platform site. CrT(⁻/y) mice showed reduced novel object recognition and conditioned fear memory compared to CrT(+/y). CrT(⁻/y) mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder.

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CrT−/y mice show deficits in object recognition memory.The novel object recognition test was conducted 1 h following familiarization. The novel object discrimination index was determined by subtracting the percent time with the familiar object from the percent time with the novel object. Data are Mean ± SEM. *P<0.05, n = 16/genotype.
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pone-0016187-g006: CrT−/y mice show deficits in object recognition memory.The novel object recognition test was conducted 1 h following familiarization. The novel object discrimination index was determined by subtracting the percent time with the familiar object from the percent time with the novel object. Data are Mean ± SEM. *P<0.05, n = 16/genotype.

Mentions: NOR is a test of short-term, hippocampally-dependent memory. CrT−/y mice spent less time attending to the novel object than CrT+/y mice [genotype (F(1,30) = 7.30, P<0.05, Figure 6)]. CrT−/y mice investigated the objects and reached the 30 s criterion, therefore, the visual system of CrT−/y mice are sufficiently intact that they can see and recognize the objects adequately to respond to them appropriately.


Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency.

Skelton MR, Schaefer TL, Graham DL, Degrauw TJ, Clark JF, Williams MT, Vorhees CV - PLoS ONE (2011)

CrT−/y mice show deficits in object recognition memory.The novel object recognition test was conducted 1 h following familiarization. The novel object discrimination index was determined by subtracting the percent time with the familiar object from the percent time with the novel object. Data are Mean ± SEM. *P<0.05, n = 16/genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3020968&req=5

pone-0016187-g006: CrT−/y mice show deficits in object recognition memory.The novel object recognition test was conducted 1 h following familiarization. The novel object discrimination index was determined by subtracting the percent time with the familiar object from the percent time with the novel object. Data are Mean ± SEM. *P<0.05, n = 16/genotype.
Mentions: NOR is a test of short-term, hippocampally-dependent memory. CrT−/y mice spent less time attending to the novel object than CrT+/y mice [genotype (F(1,30) = 7.30, P<0.05, Figure 6)]. CrT−/y mice investigated the objects and reached the 30 s criterion, therefore, the visual system of CrT−/y mice are sufficiently intact that they can see and recognize the objects adequately to respond to them appropriately.

Bottom Line: Male CrT(⁻/y) (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes.CrT(⁻/y) mice showed increased path length during acquisition and reversal learning in the Morris water maze.Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Cincinnati Children's Research Foundation, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America. Matthew.skelton@cchmc.org

ABSTRACT
Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2-4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT(⁻/y) (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT(⁻/y) mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT(⁻/y) mice showed increased average distance from the platform site. CrT(⁻/y) mice showed reduced novel object recognition and conditioned fear memory compared to CrT(+/y). CrT(⁻/y) mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder.

Show MeSH
Related in: MedlinePlus