Elsevier

Neuroscience

Volume 94, Issue 1, September 1999, Pages 185-192
Neuroscience

Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function

https://doi.org/10.1016/S0306-4522(99)00285-7Get rights and content

Abstract

Fragile X syndrome is an X-linked form of mental retardation resulting from the absence of expression of the fragile X mental retardation 1 gene. The encoded protein is a ribosome-associated, RNA-binding protein thought to play a role in translational regulation of selective messenger RNA transcripts. A knockout mouse has been described that exhibits subtle deficits in spatial learning but normal early-phase long-term potentiation. We expanded these studies by examination of late-phase hippocampal long-term potentiation, the protein synthesis-dependent form of long-term potentiation, in the Fmr1 knockout mice. Here, late-phase long-term potentiation was normal, suggesting either that absence of fragile X mental retardation protein has no influence on long-term potentiation or that any influence is too subtle to be detected by this technique. Alternatively, the hippocampus may not be the primary site affected by the absence of this protein. Accordingly, we examined spatial learning in the knockout mice using the hippocampus-dependent Morris water maze. Contrary to earlier reports, near-normal performance was observed. Since the knockout line used in this study has been back-crossed to C57BL/6 for more than 15 generations, whereas the line used in the earlier studies contained a substantial strain 129 contribution, we examined F1 siblings of knockout and 129 crosses. Here, significant but subtle increased swim latencies in reversal trials were observed, in agreement with the previous studies.

These data suggest strain differences between C57BL/6 and 129 that influence the Fmr1 knockout phenotype. In order to investigate a paradigm less dependent on hippocampal function, the knockout mice were examined using the conditional fear paradigm. Here, the knockout animals displayed significantly less freezing behavior than their wild-type littermates following both contextual and conditional fear stimuli. These data suggest that amygdala disturbances may also be involved in fragile X syndrome.

Section snippets

Subjects

Fmr1 knockout mice, from a colony founded by Fmr1 knockout animals3 kindly provided by Drs B. Oostra and P. Willems, were used. This colony had been bred to become congenic on the C57BL/6 background and at the time of this study was at least 15 generations against C57BL/6. Female heterozygous Fmr1 knockout mice3 were bred with either wild-type C57BL/6 or 129Re/J males. Only male knockout mice and their normal X chromosome male littermates were used. Knockouts and their control littermates were

Electrophysiology

Since Fmrp associates with ribosomes and may be involved in protein synthesis,2., 8., 10., 22., 48. we studied L-LTP in the Fmr1 knockout mouse, which is dependent on both protein and RNA synthesis.1., 12., 13., 14., 35., 38. In agreement with previous early LTP studies by Godfraind et al.,15 hippocampal LTP at the Schaffer collateral–CA1 synapse showed no difference in evoked responses at 120 min post-tetanus between knockout animals and their control littermates [Fig. 1; 194.7±30% (n=6) for

Electrophysiology

The studies described above expand our understanding of the mouse model for fragile X syndrome. Despite an association of Fmrp with ribosomes,10., 11., 48. no effects were observed on late phase, protein synthesis-dependent, hippocampal LTP. Although L-LTP requires intact translation,12., 38. the absence of Fmrp had no demonstrable effect on L-LTP in the knockout animals. Since fragile X patients demonstrate visual–spatial and short-term memory deficits,4., 30. and the knockout mice were

Acknowledgements

This work was supported, in part, by grants R37 HD20521 and PO1 HD35576 to S.T.W.; S.T.W. is an investigator and W.P. and H.E.M. are associates of the Howard Hughes Medical Institute.

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