A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging

Hum Mol Genet. 2016 Oct 1;25(19):4186-4200. doi: 10.1093/hmg/ddw252. Epub 2016 Jul 27.


Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / pathology
  • Animals
  • Brain / physiopathology
  • Brain Diseases, Metabolic, Inborn / genetics*
  • Brain Diseases, Metabolic, Inborn / physiopathology
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / physiopathology
  • Creatine / deficiency*
  • Creatine / genetics
  • Disease Models, Animal
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Membrane Transport Proteins / genetics*
  • Mental Retardation, X-Linked / genetics*
  • Mental Retardation, X-Linked / physiopathology
  • Mice
  • Mice, Transgenic
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency*
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics


  • Membrane Transport Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • creatine transporter
  • Creatine

Supplementary concepts

  • Creatine deficiency, X-linked