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

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 pl ay a role in translational regulation of selective messenger RNA transcript s. A knockout mouse has been described that exhibits subtle deficits in spa tial learning but normal early-phase long-term potentiation. We expanded th ese studies by examination of late-phase hippocampal long-term potentiation , the protein synthesis-dependent form of long-term potentiation, in the Fm r1 knockout mice. Here, late-phase long-term potentiation was normal, sugge sting either that absence of fragile X mental retardation protein has no in fluence 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 exami ned spatial learning in the knockout mice using the hippocampus-dependent M orris 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 earli er studies contained a substantial strain 129 contribution, we examined F1 siblings of knockout and 129 crosses. Here, significant but subtle increase d swim latencies in reversal trials were observed, in agreement with the pr evious studies. These data suggest strain differences between C57BL/6 and 129 that influenc e the Fmr1 knockout phenotype. In order to investigate a paradigm less depe ndent on hippocampal function, the knockout mice were examined using the co nditional fear paradigm. Here, the knockout animals displayed significantly less freezing behavior than their wild-type littermates following both con textual and conditional fear stimuli. These data suggest that amygdala dist urbances may also be involved in fragile X syndrome. (C) 1999 IBRO. Publish ed by Elsevier Science Ltd.