A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

Sci Rep. 2021 Jan 15;11(1):1636. doi: 10.1038/s41598-020-80824-x.


Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficits and autistic-like traits. The Slc6a8Y389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Behavior, Animal
  • Body Weight
  • Brain / metabolism*
  • Brain Diseases, Metabolic, Inborn / genetics
  • Brain Diseases, Metabolic, Inborn / pathology
  • Creatine / blood
  • Creatine / deficiency
  • Creatine / genetics
  • Disease Models, Animal
  • Female
  • Gene Knock-In Techniques
  • Genotype
  • Humans
  • Male
  • Memory, Short-Term
  • Mental Retardation, X-Linked / genetics
  • Mental Retardation, X-Linked / pathology
  • Mutation, Missense
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Plasma Membrane Neurotransmitter Transport Proteins / chemistry
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics*
  • Plasma Membrane Neurotransmitter Transport Proteins / metabolism
  • Rats


  • Nerve Tissue Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • Slc6a8 protein, rat
  • Creatine

Supplementary concepts

  • Creatine deficiency, X-linked