Trends in Genetics
Volume 19, Issue 3, March 2003, Pages 148-154
Journal home page for Trends in Genetics

Of mice and the fragile X syndrome

https://doi.org/10.1016/S0168-9525(03)00017-9Get rights and content

Abstract

Fragile X syndrome is the most common cause of inherited mental retardation, and recently a number of mouse models have been generated to study the condition. Knockout of the gene associated with fragile X, Fmr1, results in mild, but consistent abnormalities, analogous to the clinical and pathological symptoms observed in human patients. Thus, many aspects of the syndrome can now be studied in mice, taking full advantage of the benefits of this model organism, including the short generation time and unlimited supply of tissue. The experimental data suggest that knockout of Fmr1 mildly disturbs a variety of processes in different brain regions.

Section snippets

Behavioral changes in the fragile X knockout mouse

Interrupting the murine Fmr1 gene generated the first mouse model for the fragile X syndrome [16]. Although this mutation is not representative of the CGG repeat expansion, it does cause loss of FMRP production, so the result is the same in the animal model as in patients.

Morphological abnormalities of the fragile X knockout mouse model

Morphological abnormalities in male fragile X patients include an elongated face with prominent ears and macroorchidism. In the fragile X mouse model, no facial abnormalities were observed [16], but macroorchidism is significant from day 15 after birth onwards (Fig. 2), and the increase in size compared with wild type exceeds 30% at 6 months 16, 17, 20, 27, 29, 32. No structural testicular abnormalities were observed in the mice 16, 33, similarly to human patients [4], and the macroorchidism is

Electrophysiogical abnormalities might relate to the cognitive deficits

Differences in spatial memory as measured in the Morris water maze test have been associated with abnormalities in long-term potentiation (LTP). LTP is a long lasting increase in synaptic efficiency, believed to be involved in learning and memory [45]. Four independent electrophysiological studies, each using a slightly different protocol, showed no evidence for altered LTP in the CA1 region of the hippocampus of the knockout mouse 19, 46, 47, 48. By contrast, LTP appeared severely reduced when

Fragile X knockout mice are prone to epileptic seizures

Seizures occur in 22% of fragile X patients [2]. However, spontaneous seizures were never observed in fragile X knockout mice, although they can be elicited by auditory stimuli. Fragile X knockout mice were more prone to epileptic seizures than their control littermates 30, 52. The susceptibility to seizures appears age dependent, with older mice showing a higher susceptibility. Seizure induction by chemical convulsants was not successful, suggesting that the increase in seizure susceptibility

Differences between human and mouse studies: the effect of genetic background

The original fragile X mouse model was generated in a 129P2 background and was subsequently bred into two different genetic backgrounds, C57BL/6 and FVB. The variation among results from the same test methods could be due to differences in the background mouse strains. In addition, early studies were carried out before the strains were fully congenic, while they still contained varying amounts of the 129P2 background. For example, the IIPMF field was large when measured in a C57BL/6 background,

Mouse models of repeat expansion

Expansion of the repeat from generation to generation is a poorly understood phenomenon of dynamic mutations in general. Experimental evidence suggests that expansion from a pre-mutation allele to a full-sized mutation allele in fragile X syndrome occurs during oogenesis or in the first days of postzygotic development [6]. However, many questions on the behavior of the repeat remain unanswered, including why male germ cells are spared from the expansion to a full mutation [5]. As these

Double knockouts with paralogous genes might unravel hidden deficits

The FMR1 gene is a member of a gene family, and one possible explanation for the relatively mild phenotype of the fragile X syndrome is that the protein products of two autosomal paralogs of FMR1 (FXR1 and FXR2) partially compensate for FMRP. This hypothesis predicts that double or triple knockouts of FMR1, FXR1 and FXR2 will show a much more severe phenotype than knockouts of each individual gene. Although an FXR1 knockout was created several years ago, not much is known about its phenotype

Rescue of the fragile X mutation

To determine whether the fragile X syndrome is a potentially treatable disorder, several attempts have been made to rescue the silenced murine Fmr1 gene using a transgenic human FMR1 gene. Initial attempts introduced a human cDNA under control of a CMV promoter into the knockout mouse [20]. Although the overall brain FMRP was about half of that of the controls, no rescue of the phenotype was observed. This could be the consequence of the cDNA being under control of a CMV promoter, which

The fragile X syndrome could be the caused by a generalized, mild brain dysfunction

Summarizing the differences between fragile X mutant mice and controls, it seems unlikely that the cognitive problems in the fragile X mouse are caused by deficits of a single, specific brain region (Table 2, Fig. 3). Abnormalities in the spatial learning point to hippocampal abnormalities and a crucial role of this brain region is also supported by the anatomical differences in hippocampal IIPMF fields and the altered long-term synaptic plasticity. However, the differences in acoustic startle

Acknowledgments

I thank Ben Oostra and Guy Van Camp for critical reading of the manuscript, and Annemie Van der Linden for generating the MRI image. Financial support for fragile X research in Antwerp was obtained through grants of the Belgian National Fund for Scientific Research – Flanders (FWO), an Interuniversity Attraction Pole (IUAP-V), and the Fragile X Research Foundation (FRAXA).

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