Short-term selective breeding for high and low prepulse inhibition of the acoustic startle response; pharmacological characterization and QTL mapping in the selected lines.

Selective breeding offers several important advantages over using inbred strain panels in detecting genetically correlated traits to the selection phenotype. The purpose of the current study was to selectively breed for prepulse inhibition (PPI) of the acoustic startle response (ASR), to pharmacologically and behaviorally characterize the selected lines and to use the lines for quantitative trait loci (QTL) mapping. Starting with heterogeneous stock mice formed by crossing the C57BL/6J, DBA/2J, BALB/cJ and LP/J inbred strains and using a short-term selective breeding strategy, animals were selected for High and Low PPI. The selection phenotype was the 80 dB prepulse tone (15 dB above the background noise). After five generations of selection, the High and Low lines differed significantly (78.1 +/- 3.1 vs. 45.2 +/- 3.9 [percent inhibition], p < 0.00001). The effects of haloperidol and MK-801 on PPI were not different between the High and Low lines. However, at the highest dose tested (10 mg/kg), the High line was more sensitive than the Low line to the disruptive PPI effects of methamphetamine. The lines did not differ in terms of basal activity or methamphetamine-induced changes in locomotor activity. The High and Low lines were genotyped using a panel of 768 SNPs. Significant QTLs (LOD > 10) were detected on chromosomes 11 and 16 that appeared similar to those detected previously [Hitzemann, R., Bell, J., Rasmussen, E., McCaughran, J. Mapping the genes for the acoustic startle response (ASR) and prepulse inhibition of the ASR in the BXD recombinant inbred series: effect of high-frequency hearing loss and cochlear pathology. In: Willott JF, editor. Handbook of mouse auditory research: From behavior to molecular biology. New York: CRC Press; 2001, p. 441-455.; Petryshen, T. L, Kirby, A., Hammer, R.P. Jr, Purcell, S., O'Leary, S.B., Singer, J.B., et al. Two quantitative trait loci for prepulse inhibition of startle identified on mouse chromosome 16 using chromosome substitution strains. Genetics 2005; 171: 1895-1904.]. Overall, the current study illustrates that the heritability of PPI is sufficient for shortterm selective breeding and that the lines which are developed can be used to characterize the factors associated with the regulation of PPI.