Genomic survey of prepulse inhibition in mouse chromosome substitution strains |
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| Authors: | M P Leussis M L Frayne M Saito E M Berry K A Aldinger G N Rockwell R P Hammer Jr A E Baskin-Hill J B Singer J H Nadeau P Sklar T L Petryshen |
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| Institution: | Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Departments of Basic Medical Sciences and Pharmacology, University of Arizona College of Medicine, Phoenix, AZ; Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH; , and Clinical Pharmacogenetics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA |
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| Abstract: | Prepulse inhibition (PPI) is a measure of sensorimotor gating, a pre-attentional inhibitory brain mechanism that filters extraneous stimuli. Prepulse inhibition is correlated with measures of cognition and executive functioning, and is considered an endophenotype of schizophrenia and other psychiatric illnesses in which patients show PPI impairments. As a first step toward identifying genes that regulate PPI, we performed a quantitative trait locus (QTL) screen of PPI phenotypes in a panel of mouse chromosome substitution strains (CSSs). We identified five CSSs with altered PPI compared with the host C57BL/6J strain: CSS-4 exhibited decreased PPI, whereas CSS-10, -11, -16 and -Y exhibited higher PPI compared with 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. Quantitative trait loci 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 101.5 and 114.4 Mb (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. |
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| Keywords: | Behavior cognition linkage mouse genetics psychiatric disorders psychopathology quantitative trait locus sensorimotor gating startle |
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