Selective Breeding of Reduced Sensorimotor Gating in Wistar Rats

Abstract

Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is reduced in some neuropsychiatric disorders (e.g. schizophrenia). Animal models have revealed insight into the neuronal and pharmacological underpinnings of PPI-deficits. Recent work has shown that a PPI-deficit can be selectively bred in Wistar rats and is already stable in the second filial generation. We here report on developmental and parametric characteristics of sensorimotor gating deficits in the 4th and 6th filial generation of male rats selectively bred for low PPI (low PPI) compared to rats with normal levels of PPI (high PPI). Low PPI rats showed significantly reduced PPI and variable startle magnitude (in pulse alone trials) along with reduced short-term habituation of startle as adults. Reduced PPI in the low PPI rats was found throughout development (tested on postnatal days 21, 35, 49, 70). PPI-deficits in the low PPI rats were evident at prepulse intensities ranging from 62-86 dB and for interstimulus intervals ranging between 30-1000 ms. These behavioral data add to a growing body of knowledge about the genetic basis of sensorimotor gating deficits and suggest that low PPI rats have potential use as an intermediate phenotype in schizophrenia research. The stable phenotype of breeding-induced PPI-deficits and reduced startle habituation indicates that PPI has strong genetic determinants and that selectively bred rats can be used for future neurophysiological, anatomical, pharmacological, and genomic analyses.

Neural correlates of sensorimotor gating: a metabolic positron emission tomography study in awake rats

“…So far, invasive methods such as brain lesions, substance administration, electrical stimulation (Swerdlow et al, 2001a) and genetic approaches like selective breeding, inbred strain comparisons and mutant analysis (Swerdlow et al, 2000; Geyer et al, 2002; Schwabe et al, 2007) served to study brain circuitries regulating startle and PPI. The proposed pathway mediating PPI of acoustic startle comprises inferior and superior colliculus, pedunculopontine and laterodorsal tegmental nuclei as well as substantia nigra.…”

Are DBA/2 mice associated with schizophrenia-like endophenotypes? A behavioural contrast with C57BL/6 mice

“…One approach is to develop selective breeding (e.g. Logue et al 1997;McCaughran et al 1997;Schwabe et al 2007), whilst another is to compare existing, usually inbred strains with relatively stable genetic backgrounds (Bullock et al 1997;Crawley et al 1997;Paylor and Crawley 1997). The inbred DBA/2 mouse strain has attracted interests recently in its potential relevance to psychosis-related traits in comparison to another common inbred mouse strain-the C57BL/6 strain-as the reference line (Olivier et al 2001;Spielewoy and Markou 2004).…”

Development and characterization of chronic animal models of schizophrenia

“…Several studies used the selective-breeding procedures to develop new lines (or strains) of rats in psychiatric disorders such as epilepsy, depression or schizophrenia. Schwabe et al have shown that a PPI-deficit can be selectively bred in Wistar rats and is already stable in the second filial generation [5]. Cognitive abilities also show a significant inheritance, as indicated by earlier experiments in selectively bred rats [44].…”

“…Sensory gating, as a non specific sign, is reduced in a variety of neuropsychiatric disorders (e.g. Huntingtons's disease, Tourette's syndrome, autism, bipolar or panic disorder) including schizophrenia [3][4][5].…”

“…It is assumed that changes in the prefrontal cortex after social isolation and/or imbalances between neural connections within the cortico-striato-limbic circuitry lead to the observed PPI disturbances [4]. Disturbed PPI as a result of selective breeding, was proven to be heritable, and this can be used to develop an animal model for schizophrenia [5,[144][145][146][147]. The rats with impaired PPI also exhibited deteriorated social behavior, impaired reward responses, and abnormalities in information processing; which indicates that rats with low PPI show other schizophrenia-like disturbances, as well.…”