Genomic survey of prepulse inhibition in mouse chromosome substitution strains

Abstract

Prepulse inhibition (PPI) is a measure of sensorimotor gating, a pre-attentional inhibitory brain mechanism that filters extraneous stimuli. PPI is correlated with measures of cognition and executive functioning, and is considered an endophenotype of schizophrenia and other psychiatric illnesses in which patients demonstrate PPI impairments. As a first step towards identifying genes that regulate PPI, we performed a quantitative trait locus (QTL) screen of PPI phenotypes in a panel of mouse chromosome substitution strains (CSS). We identified five CSSs with altered PPI compared to the host C57BL/6J strain: CSS-4 exhibited decreased PPI, whereas CSS-10, -11, -16, and -Y exhibited higher PPI compared to C57BL/6J. These data indicate that A/J chromosomes 4, 10, 11, 16, and Y harbor at least one QTL region that modulates PPI in these CSSs. QTLs for the acoustic startle response were identified on seven chromosomes. Like PPI, habituation of the startle response is also disrupted in schizophrenia, and in the present study CSS-7 and -8 exhibited deficits in startle habituation. Linkage analysis of an F2 intercross identified a highly significant QTL for PPI on chromosome 11 between positions 101.5Mb – 114.4Mb (peak LOD = 4.54). Future studies will map the specific genes contributing to these QTLs using congenic strains and other genomic approaches. Identification of genes that modulate PPI will provide insight into the neural mechanisms underlying sensorimotor gating, as well as the psychopathology of disorders characterized by gating deficits.

Fine mapping of QTL for prepulse inhibition in LG/J and SM/J mice using F2 and advanced intercross lines

“…The other three studies used F 2 crosses between B6 and A/J (Joober et al 2002), B6 and C3H/He (Watanabe et al 2007) and B6 and DBA/2J (Hitzemann et al 2008). The A/J allele on chromosome 11 was associated with elevated levels of PPI compared with B6 (Joober et al 2002; Leussis et al 2009), whereas Hitzemann et al (2008) found that the B6 was associated with elevated PPI over DBA/2J. Taken together, these data suggest that the QTL we observed on chromosome 11 may or may not be because of the same alleles as previously reported QTLs for PPI on chromosome 11.…”

“…Watanabe et al (2007) had a peak around 65.9 megabases (Mb), which is likely to be different from our QTL that was located between 103 and 115 Mb. The study by Leussis et al (2009) found that CSS‐7 had an elevated startle response and CSS‐17 had a lower startle response in comparison to B6 mice; however, their study did not attempt to further localize these peaks.…”

Acoustic startle modification as a tool for evaluating auditory function of the mouse: Progress, pitfalls, and potential

“…Several studies have identified quantitative trait loci that are thought to be related to PPI strength in mice. These include areas on chromosomes 2, 3, 4, 5, 7, 10, 11, 12, 16, and 17 (Joober et al 2002; Petryshen et al 2005; Leussis et al 2009; Samocha et al 2010; Loos et al 2012). Takata et al (2010) found that Uqcr10 and Nipsnap1 located on chromosome11qA1 are candidate genes for PPI.…”

A verification of previously identified QTLs for cocaine-induced activation using a panel of B6.A chromosome substitution strains (CSS) and A/J x C57Bl/6J F2 mice

“…The use of CSSs provides a statistically powerful approach for examining the genetic architecture of complex traits (Shao et al 2008). The B6.A CSS strains have been used as a simple, rapid method of determining the chromosomal location of QTLs (Nadeau et al 2000) for several complex traits, including prepulse inhibition (Leussis et al 2009), sensitivity to methamphetamine (Bryant et al 2009), anxiety (Singer et al 2004), and cancer (Youngren et al 2003). Methodologically, the CSS model has been demonstrated to be more efficient than traditional crosses in that it requires the testing of fewer progeny to detect a specific effect, or allows smaller effects to be detected with a given number of subjects (Belknap 2003).…”