Cognitive decline, neuromotor and behavioural disturbances in a mouse model for fragile-X-associated tremor/ataxia syndrome (FXTAS)

Behav Brain Res. 2005 Jul 30;162(2):233-9. doi: 10.1016/j.bbr.2005.03.007.

Abstract

Carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are spared the major neurodevelopmental symptomatology of fragile X syndrome patients carrying a full mutation (>200 repeats). In a proportion of premutation carriers, the repeat expansion is associated with a specific neurological profile involving intention tremor, ataxia, intellectual decline compatible with dementia syndrome, Parkinsonism and autonomic dysfunction at older age, commonly referred to as fragile-X-associated tremor/ataxia syndrome (FXTAS). Typical CNS changes include hyperintense signals on T2 weighted magnetic resonance images and the presence of ubiquitin-positive intranuclear neuronal inclusions. A knock-in mouse model with a (CGG)98 repeat in the premutation range has been generated and shown to exhibit elevated Fmr1 mRNA levels and ubiquitin-positive intranuclear neuronal inclusions, suggesting it may be a valid model for the human disease. Given the specific clinical profile of FXTAS patients, the expanded CGG repeat model was assessed for cognitive, behavioural and neuromotor performance at different ages (20, 52 and 72 weeks). The Morris water maze task exposed age-dependent decline of visual-spatial memory. Open field recordings revealed decreased exploration of the centre of the arena in the oldest group of expanded CGG repeat mice, potentially reflecting increased anxiety. Neuromotor tasks primarily showed decline of performance on the accelerating rotarod with age in the premutation carriers but not in control littermates. The age-dependent cognitive decline and neuromotor disturbances may be related to the progressive cognitive and behavioural difficulties observed in FXTAS patients.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Behavior, Animal / physiology*
  • Cognition Disorders / etiology*
  • Cognition Disorders / genetics
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Female
  • Fragile X Syndrome / complications*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / physiopathology*
  • Gait / genetics
  • Gait / physiology
  • Humans
  • Mental Disorders / etiology*
  • Mental Disorders / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Neuron Disease / etiology*
  • Motor Neuron Disease / genetics
  • Psychomotor Performance / physiology
  • Rotarod Performance Test / methods
  • Trinucleotide Repeat Expansion / genetics