Effect of genetic background on acoustic startle response in fragile X knockout mice

To study the effect of genetic background on the Fmr1 knockout mutation in mice, we compared the acoustic startle response (ASR) of male fragile X knockout mice bred in three different genetic backgrounds, including C57BL/6J (C57BL/6J x 129P2/OlaHsd) F1 and F2 intercross. ASR is used as a behavioural tool to assess the neuronal basis of behavioural plasticity. For each background studied, fragile X knockouts clearly differed in ASR from their control littermates. C57BL/6J knockouts showed an increase in ASR in response to the lowest stimulus of 90 dB and a decrease in ASR in response to the highest stimulus of 110 dB when compared with control mice, whereas knockouts of the F1 generation showed significantly lower ASRs for all the three stimulus intensities used when compared with control littermates. These data demonstrate that the expression of the fragile X phenotype in ASR of fragile X knockout mice may be influenced by the presence of 129 genes in the genetic background and that modifier genes may influence the fragile X phenotype. Surprisingly, and in contrast with knockouts of the F1 generation that showed a decreased ASR, knockouts of the F2 generation showed a significantly increased ASR compared with their control littermates. This is especially remarkable as both F1 and F2 mice consist of 50% of the genetic material from each of the parental strains C57BL/6J and 129P2/OlaHsd strain. Thus, the different distribution of the genetic background seems to be responsible for the difference in ASR between F1 and F2. This opposite ASR in the F1 and F2 generations is unique in behavioural studies and has, to our knowledge, not been previously reported.