Systematic approaches to identifying novel behavioural mutations using ENU mutagenesis.

Chemical mutagenesis represents an efficient phenotype-driven approach to deriving new mutations for the mouse mutant catalogue. However, a systematic approach to increasing the mouse mutant resource will include the development of many novel phenotypic screens. The incorporation of established behavioural screens is expected to increase our understanding of the genetic basis of mammalian behaviour and its application in human neurological and psychiatric disorders. We have initiated a genome-wide screen for dominant mutations in mice. ENU-mutagenised BALB/c males are being mated to C3H females and up to 40,000 F1 progeny characterised using the SHIRPA protocol (Rogers et al., Mammalian Genome, (1997) 8(10): 711). SHIRPA is a hierarchical screening protocol employing a rapid and efficient primary screen for deficits in muscle and lower motor neurone function, spinocerebellar function, sensory function, neuropsychiatric function and autonomic function. Subsequently, these mice are being screened further using two well-established behavioural tests, specifically chosen in that they may measure defects in parameters associated with human psychiatric disorders. Locomotor activity (LMA) is measured by adding mice to cages equipped with beam-splitting monitors. This apparatus allows us to measure general activity status of mice and to calculate the habituation of mice to their novel environment. LMA is recorded over a 35 minute test period in bins of 5 minutes duration. Prepulse inhibition of the acoustic startle response (PPI) is also measured. The acoustic startle is an exaggerated response to unexpected auditory stimuli and this is normally reduced when preceded by a weaker prestimulus - PPI. Acoustic startle and PPI are measured over a range of sound amplitudes and frequencies and average responses are calculated. To date, we have screened over 2,000 F1 mice in both LMA and PPI paradigms, all of which have been previously characterised using the SHIRPA phenotypic assessment. The results show, for each behavioural test, that we can detect consistently abnormal behaviours (> 3 standard deviations from the population mean) in approximately 1% of all mice screened. Inheritance of abnormal behaviour is being determined in mice backcrossed to C3H