The effects of Eph–ephrin mutations on pre-pulse inhibition in mice

• Eph-ephrin mutations affect pre-pulse inhibition (PPI) when compared to controls.
• Heterozygous EphA4lacZ/+ mice showed a normal startle response and normal PPI. Ephrin-B3null mice showed a normal startle response, but little PPI. Homozygous EphA4lacZ/lacZ mice showed a diminished startle response and diminished PPI.
• The pattern of responses to the pre-pulse and to the startling stimulus is different in various mutations suggesting complex alterations of the psychometric function due to Eph-ephrin mutations.
• Previously published data in control and wild-type mice support present findings.

Eph–ephrin signaling is known to be important in directing topographic projections in the afferent auditory pathway, including connections to various subdivisions of the inferior colliculus (IC). The acoustic startle-response (ASR) is a reliable reflexive behavioral response in mammals elicited by an unexpected intense acoustic startle-eliciting stimulus (ES). It is mediated by a sub-cortical pathway that includes the IC. The ASR amplitude can be measured with an accelerometer under the subject and can be decreased in amplitude by presenting a less intense, non-startling stimulus 5–300 ms before the ES. This reflexive decrement in ASR is called pre-pulse inhibition (PPI) and indicates that the relatively soft pre-pulse was heard. PPI is a general trait among mammals. Mice have been used recently to study this response and to reveal how genetic mutations affect neural circuits and hence the ASR and PPI. In this experiment, we measured the effect of Eph–ephrin mutations using control mice (C57BL/6 J), mice with compromised EphA4 signaling (EphA4lacZ/+, EphA4lacZ/lacZ), and knockout ephrin-B3 mice (ephrin-B3 +/−, −/−). Control and EphA4lacZ/+ strains showed robust PPI (up to 75% decrement in ASR) to an offset of a 70 dB SPL background noise at 50 ms before the ES. Ephrin-B3 knockout mice and EphA4 homozygous mutants were only marginally significant in PPI (< 25% decrement and < 33% decrement, respectively) to the same conditions. This decrement in PPI highlights the importance of ephrin-B3 and EphA4 interactions in ordering auditory behavioral circuits. Thus, different mutations in certain members of the signaling family produce a full range of changes in PPI, from minimal to nearly maximal. This technique can be easily adapted to study other aspects of hearing in a wider range of mutations. Along with ongoing neuroanatomical studies, this allows careful quantification of how the auditory anatomical, physiological and now behavioral phenotype is affected by changes in Eph–ephrin expression and functionality.