Of Men and Mice: Modeling the Fragile X Syndrome

Abstract

The Fragile X Syndrome (FXS) is one of the most common forms of inherited intellectual disability in all human societies. Caused by the transcriptional silencing of a single gene, the fragile x mental retardation gene FMR1, FXS is characterized by a variety of symptoms, which range from mental disabilities to autism and epilepsy. More than 20 years ago, a first animal model was described, the Fmr1 knock-out mouse. Several other models have been developed since then, including conditional knock-out mice, knock-out rats, a zebrafish and a drosophila model. Using these model systems, various targets for potential pharmaceutical treatments have been identified and many treatments have been shown to be efficient in preclinical studies. However, all attempts to turn these findings into a therapy for patients have failed thus far. In this review, I will discuss underlying difficulties and address potential alternatives for our future research.

Keywords: E/I balance; FMR1; Fragile X Syndrome; autism spectrum disorders; behavior and cognition; microsatellite instability; mouse model; primates.

Figure 1

The FXS world. The drawing illustrates factors influencing the disease. A characteristic of FXS is the presence of a broad range of deficits with a high degree of individual variation. The phenotype of the disorder includes cognitive disabilities as well as autistic behaviors and epilepsy. Aside from a loss of FMRP expression, the genetic background and environmental factors are emerging as determinants of the disease. However, while residual FMRP expression is known to correlate with the cognitive performance of FXS patients, the impact of individual genes and the relevance of the environment are less well understood (also see the section “Phenotype”). Recent findings indicate that autistic behaviors and epilepsy are influenced by the E/I balance, but not by residual FMRP expression. FXS, Fragile X Syndrome; FMRP, Fragile X Mental Retardation Protein; E/I balance, balance of excitation and inhibition in neuronal networks.

Figure 2

FMR1^−/y diseases. The scheme shows the relation between microsatellite length (number of repeats) and phenotype. While healthy individuals show 6–44 tandem tracts in the 5′ UTR of their FMR1 gene, FXS patients display more than 200 repeats. Alleles containing 45–54 repeats are classified as intermediate, and 55–200 repeats as pre-mutation alleles. Premutation alleles give rise to a neurodegenerative disorder called FXTAS, which presents with parkinsonism and brain atrophy. FXTAS typically manifests in individuals over the age of 50. FMR1: Fragile X Mental Retardation gene. FMRP: Fragile X Mental Retardation Protein. FXS: Fragile X Syndrome. FXTAS: Fragile X-associated Tremor/Ataxia Syndrome. E/I balance: balance of excitation and inhibition in neuronal networks, UTR: untranslated region. ↓: decreased levels in the diseased condition. ↔ similar levels in normal and diseased conditions. ↑ increased levels in diseased conditions.

Figure 3

A comparison of FXS in mice and men. The figure summarizes some major differences between FXS model mice and patients. Most differences arise from the development of the cortex in primates, which caused a rewiring inside the cortex as well as between the cortex and the hippocampus (and potentially other brain regions). Consequently, the behavioral phenotype observed in men and mice does not match very well, although the mouse model recapitulates many biochemical aspects of the disease. In addition, the complex genetics of the disease cannot be modeled in mice, probably due to a more relaxed gene expression control in this species.