Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring

Sartini, Stefania; Lattanzi, Davide; Ambrogini, Patrizia; Palma, Michael Di; Galati, Claudia; Savelli, David; Polidori, Emanuela; Calcabrini, Cinzia; Rocchi, Marco; Sestili, Piero; Cuppini, Riccardo

doi:10.1016/j.neuroscience.2015.11.017

Cited by 18 publications

(24 citation statements)

References 66 publications

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“…35 In addition, maternal Cr supplementation in rats enhanced hippocampal neuron development and improved long-term potentiation. 36 Taken together, these data suggest that using Nestin-cre mice to generate brain-specific Slc6a8 disruption is more comparable to the ubiquitous Slc6a8 −/y mice.…”

Section: Discussionmentioning

confidence: 71%

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

Udobi

Kokenge

Hautman

et al. 2018

Genes Brain and Behavior

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Creatine 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 (Slc6a8 ) mice to create ubiquitous Slc6a8 knockout (Slc6a8 ) mice. Slc6a8 mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8 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 Slc6a8 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 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 mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8 mice.

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Section: Discussionmentioning

confidence: 71%

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

Udobi

Kokenge

Hautman

et al. 2018

Genes Brain and Behavior

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show abstract

“…The importance of Cr in brain development has been highlighted recently in a study showing that the loss of Cr kinase leads to aberrant neuronal development (Fukumitsu et al, 2015). In addition, maternal Cr supplementation in rats enhanced hippocampal neuron development and improved longterm potentiation (Sartini et al, 2016). Taken together, the use of Nestin-cre mice to generate brain-specific Slc6a8 disruption shows a phenotype more comparable to the ubiquitous Slc6a8 -/y mice.…”

Section: Discussionmentioning

confidence: 97%

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

Udobi

Kokenge

Hautman

et al. 2017

Preprint

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(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/196063 doi: bioRxiv preprint first posted online Sep. 29, 2017; 2 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 (Slc6a8 flox ) mice to create

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“…Since low glutamine levels were reported as early as post‐natal day of life (P) 3, we postulated that glutamine deficiency occurred already during fetal life and chose to begin supplementation during the prenatal period via maternal supplementation, with continuation throughout weaning and until P30. Prenatal supplementation of nutrients and other amino acids has proven to be effective in other animal studies in the literature . We also predicted a successful trans‐placental transfer of maternal glutamine due to the abundant number of glutamine transporters on the placental barrier …”

Section: Introductionmentioning

confidence: 89%

“…Prenatal supplementation of nutrients and other amino acids has proven to be effective in other animal studies in the literature. [9][10][11][12] We also predicted a successful trans-placental transfer of maternal glutamine due to the abundant number of glutamine transporters on the placental barrier. [13][14][15] 2 | METHODS…”

Section: Introductionmentioning

confidence: 97%

Maternal glutamine supplementation in murine succinic semialdehyde dehydrogenase deficiency, a disorder of γ‐aminobutyric acid metabolism

Brown

Walters

Schmidt

et al. 2019

J of Inher Metab Disea

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Murine succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with high concentrations of γ‐aminobutyric acid (GABA) and γ‐hydroxybutyrate (GHB) and low glutamine in the brain. To understand the pathogenic contribution of central glutamine deficiency, we exposed aldh5a1−/− (SSADHD) mice and their genetic controls (aldh5a1+/+) to either a 4% (w/w) glutamine‐containing diet or a glutamine‐free diet from conception until postnatal day 30. Endpoints included brain, liver and blood amino acids, brain GHB, ataxia scores, and open field testing. Glutamine supplementation did not improve aldh5a1−/− brain glutamine deficiency nor brain GABA and GHB. It decreased brain glutamate but did not change the ratio of excitatory (glutamate) to inhibitory (GABA) neurotransmitters. In contrast, glutamine supplementation significantly increased brain arginine (30% for aldh5a1+/+ and 18% for aldh5a1−/− mice), and leucine (12% and 18%). Glutamine deficiency was confirmed in the liver. The test diet increased hepatic glutamate in both genotypes, decreased glutamine in aldh5a1+/+ but not in aldh5a1−/−, but had no effect on GABA. Dried bloodspot analyses showed significantly elevated GABA in mutants (approximately 800% above controls) and decreased glutamate (approximately 25%), but no glutamine difference with controls. Glutamine supplementation did not impact blood GABA but significantly increased glutamine and glutamate in both genotypes indicating systemic exposure to dietary glutamine. Ataxia and pronounced hyperactivity were observed in aldh5a1−/− mice but remained unchanged by the diet intervention. The study suggests that glutamine supplementation improves peripheral but not central glutamine deficiency in experimental SSADHD. Future studies are needed to fully understand the pathogenic role of brain glutamine deficiency in SSADHD.

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Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring

Cited by 18 publications

References 66 publications

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

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

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

Maternal glutamine supplementation in murine succinic semialdehyde dehydrogenase deficiency, a disorder of γ‐aminobutyric acid metabolism

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