Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?

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While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood–brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood–brain barrier has a limited permeability for peripheral creatine. The first creatine deficiency syndrome in humans was also discovered 20 years ago (GAMT deficiency), followed later by AGAT and SLC6A8 deficiencies, all three diseases being characterized by creatine deficiency in the CNS and essentially affecting the brain. By reviewing the numerous and latest experimental studies addressing creatine transport and synthesis in the CNS, as well as the clinical and biochemical characteristics of creatine-deficient patients, our aim was to delineate a clearer view of the roles of the blood–brain and blood-cerebrospinal fluid barriers in the transport of creatine and guanidinoacetate between periphery and CNS, and on the intracerebral synthesis and transport of creatine. This review also addresses the question of guanidinoacetate toxicity for brain cells, as probably found under GAMT deficiency.

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Acetylcholine esterase


Arginine, glycine amidinotransferase


AMP-activated protein kinase




Blood–brain barrier


Blood–CSF barrier


Cerebral creatine deficiency syndromes


Creatine kinase


Central nervous system






Cerebrospinal fluid




γ-Amino butyric acid


GABAA and GABAB receptors


Glutamic acid decarboxylase


Guanidinoacetate methyltransferase




Intellectual/development delays


Microcapillary endothelial cells


Monocarboxylate transporter 12


Magnetic resonance spectroscopy






Phosphorylated GAA


Serum/glucocorticoid-regulated kinase


Creatine transporter


Taurine transporter


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Our work is supported by the Swiss National Science Foundation, Grants 3100A0-116859 and 31003A-130278.

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Correspondence to Olivier Braissant.

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The authors declare that they have no conflict of interest.

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Handling Editor: T. Wallimann and R. Harris.

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Hanna-El-Daher, L., Braissant, O. Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?. Amino Acids 48, 1877–1895 (2016).

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  • Brain
  • Creatine
  • Guanidinoacetate
  • Blood brain barrier
  • Creatine deficiency syndromes
  • AGAT
  • GAMT
  • SLC6A8