Early mitochondrial abnormalities in hippocampal neurons cultured from Fmr1 pre-mutation mouse model

J Neurochem. 2012 Nov;123(4):613-21. doi: 10.1111/j.1471-4159.2012.07936.x. Epub 2012 Sep 28.


Pre-mutation CGG repeat expansions (55-200 CGG repeats; pre-CGG) within the fragile-X mental retardation 1 (FMR1) gene cause fragile-X-associated tremor/ataxia syndrome in humans. Defects in neuronal morphology, early migration, and electrophysiological activity have been described despite appreciable expression of fragile-X mental retardation protein (FMRP) in a pre-CGG knock-in (KI) mouse model. The triggers that initiate and promote pre-CGG neuronal dysfunction are not understood. The absence of FMRP in a Drosophila model of fragile-X syndrome was shown to increase axonal transport of mitochondria. In this study, we show that dissociated hippocampal neuronal culture from pre-CGG KI mice (average 170 CGG repeats) express 42.6% of the FMRP levels and 3.8-fold higher Fmr1 mRNA than that measured in wild-type neurons at 4 days in vitro. Pre-CGG hippocampal neurons show abnormalities in the number, mobility, and metabolic function of mitochondria at this early stage of differentiation. Pre-CGG hippocampal neurites contained significantly fewer mitochondria and greatly reduced mitochondria mobility. In addition, pre-CGG neurons had higher rates of basal oxygen consumption and proton leak. We conclude that deficits in mitochondrial trafficking and metabolic function occur despite the presence of appreciable FMRP expression and may contribute to the early pathophysiology in pre-CGG carriers and to the risk of developing clinical fragile-X-associated tremor/ataxia syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Cells, Cultured
  • Fragile X Mental Retardation Protein / genetics*
  • Hippocampus / cytology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Mitochondria / physiology
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / ultrastructure*
  • Organic Chemicals / metabolism
  • Oxygen Consumption
  • RNA, Messenger / metabolism
  • Trinucleotide Repeat Expansion / genetics*


  • MitoTracker Red 580
  • Organic Chemicals
  • RNA, Messenger
  • Fragile X Mental Retardation Protein