Neuregulin-1 immunoglobulin-like domain mutant mice: Clozapine sensitivity and impaired latent inhibition

Department of Psychology, University of Texas at Austin, Austin, Texas, United States
Neuroreport (Impact Factor: 1.64). 03/2005; 16(3):271-5. DOI: 10.1097/00001756-200502280-00014
Source: PubMed

ABSTRACT Genetic and behavioral studies in humans and mouse mutants have implicated the gene encoding neuregulin-1 (Nrg-1) as a candidate susceptibility gene for schizophrenia. We examined the behavior of mice heterozygous for a mutation in neuregulin-1's immunoglobulin (Ig)-like domain (Ig-nrg-1 mice). We found that these animals displayed behaviors related to a schizophrenia-like phenotype, such as clozapine suppression of open-field and running wheel activity and impaired latent inhibition. Contrary to findings with other nrg-1 mutants, Ig-nrg-1 mice did not exhibit significantly elevated locomotion relative to littermate controls. These results suggest that Ig-Nrg-1's contribute to some - but not all - aspects of the schizophrenia-like phenotype of nrg-1 mutants, and further support nrg-1 as a candidate gene for schizophrenia.

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Available from: F. Gonzalez-Lima, Jun 08, 2015
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    • "With respect to phenotypic comparisons with more isoform-specific NRG1 deletions, type III NRG1 mutants show greater PPI impairment relative to TM-NRG1 mutants (Chen et al., 2008b). Mutants with targeted disruption of type I/type II NRG1 do not show a hyperactive phenotype (Chen et al., 2007; Rimer et al., 2005). Mutants with partial deletion in the EGF-like domain (pan-isoform) demonstrated a transitory increase in locomotor activity, and more rapid habituation, of exploration in a novel environment. "
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    ABSTRACT: Mutant mice play an increasingly important role in understanding disease processes at multiple levels. In particular, they illuminate the impact of risk genes for disease on such processes. This article reviews recent advances in the application of mutant mice to study the intricacies of dopaminergic (DAergic) function in relation to the putative pathophysiology of psychotic illness, particularly schizophrenia, and antipsychotic drug action. It considers models for understanding the role(s) of risk genes, with a particular focus on DTNBP1 and NRG1, their interactions with environmental factors, and with each other (epistasis). In overview, it considers new schemas for understanding psychotic illness that integrate DAergic pathophysiology with developmental, social, and cognitive processes, and how mutant mouse models can reflect and inform on such schemas.
    Progress in brain research 01/2014; 211:79-112. DOI:10.1016/B978-0-444-63425-2.00004-0 · 5.10 Impact Factor
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    • "The NRG1 SNP8NRG221533 (rs35753505) has most widely been evaluated in relation to cognition (Kurnianingsih et al., 2011). A role for NRG1 in SZ has also been supported by animal studies using NRG1 and ErbB4 mutant mice (Gerlai et al., 2000; Stefansson et al., 2002; Bao et al., 2003; Corfas et al., 2004; Steinthorsdottir et al., 2004; Gu et al., 2005; Rimer et al., 2005), which exhibit behaviors similar to those of established rodent models of SZ (Lipska, 2004). NRG1 polymorphisms have been proposed as risk factors for several other common disorders, including Alzheimer's disease (Chaudhury et al., 2003; Go et al., 2005); epilepsy (early myoclonic encephalopathy; Backx et al., 2009), stroke (Shyu et al., 2004; Xu et al., 2004) breast cancer (Raj et al., 2001), multiple sclerosis (Cannella et al., 1999; Viehover et al., 2001), bipolar disorder (Thomson et al., 2007; Goes et al., 2008; Prata et al., 2009; Walker et al., 2010; Moon et al., 2011) and Hirschsprung Disease (Garcia-Barcelo et al., 2009; Tang et al., 2011). "
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    ABSTRACT: BACKGROUND: Neuregulin-1 (NRG1) gene polymorphisms have been proposed as risk factors for several common disorders. Associations with cognitive variation have also been tested. With regard to schizophrenia (SZ) risk, studies of Caucasian ancestry samples indicate associations more consistently than East Asian samples, suggesting heterogeneity. To exploit the differences in linkage disequilibrium (LD) structure across ethnic groups, we conducted a SZ case-control study (that included cognitive evaluations) in a sample from the north Indian population. METHODS: NRG1 variants (n=35 SNPs, three microsatellite markers) were initially analyzed among cases (DSM IV criteria, n=1007) and controls (n=1019, drawn from two groups) who were drawn from the same geographical region in North India. Nominally significant associations with SZ were next analyzed in relation to neurocognitive measures estimated with a computerized neurocognitive battery in a subset of the sample (n=116 cases, n=170 controls). RESULTS: Three variants and one microsatellite showed allelic association with SZ (rs35753505, rs4733263, rs6994992, and microsatellite 420M9-1395, p≤0.05 uncorrected for multiple comparisons). A six marker haplotype 221121 (rs35753505-rs6994992-rs1354336-rs10093107-rs3924999-rs11780123) showed (p=0.0004) association after Bonferroni corrections. Regression analyses with the neurocognitive measures showed nominal (uncorrected) associations with emotion processing and attention at rs35753505 and rs6994992, respectively. CONCLUSIONS: Suggestive associations with SZ and SZ-related neurocognitive measures were detected with two SNPs from the NRG1 promoter region in a north Indian cohort. The functional role of the alleles merits further investigation.
    Schizophrenia Research 01/2013; 144(1-3). DOI:10.1016/j.schres.2012.12.017 · 4.43 Impact Factor
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    • "EGF-like domain of Nrg1 (C57BL/6 X 129); Females [32] Unaltered ASR No PPI deficit EGF-like domain of Nrg1 (C57BL/6 X 129/SVEV); males [33] ASR not investigated PPI not investigated Immunoglobulin-like domain Nrg1 (129/SV); males [35] ASR not investigated PPI not investigated Cysteine-rich domain Nrg1 (C57BL/6); Sex not specified [36] ASR not investigated PPI not investigated Type I Nrg1 over-expression (background not described); sex not specified [34] ASR not investigated PPI not investigated Type III Nrg1 over-expression (background not described); sex not specified [34] ASR not investigated PPI not investigated Type III Nrg1 (C57BL/6 X 129); males [28] "
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    ABSTRACT: Evidence suggests that the heterozygous transmembrane domain mutant mouse model for the schizophrenia candidate gene neuregulin 1 (Nrg1 HET) exhibits a deficit in prepulse inhibition (PPI). However, not all mouse models for Nrg1 exhibit PPI deficits. Thus, our study intended to clarify the severity of the initially described PPI deficit in Nrg1 HET mice. For this, Nrg1 mutant mice and wild type-like littermates of one breeding colony were tested for PPI in four different phenotyping facilities in Australia employing a variety of different PPI protocols with fixed and variable interstimulus intervals (ISIs). Testing mutant and wild type-like mice in three Australian phenotyping facilities using PPI protocols with variable ISIs revealed no effect of mutant transmembrane domain Nrg1 on sensorimotor gating. Changes to the startle response and startle response habituation were site/protocol-specific. The employment of two different PPI protocols at the same phenotyping facility revealed a protocol-dependent and site-specific facilitation of PPI in Nrg1 mutant mice compared to wild type-like mice. In conclusion, the often-noted PPI phenotype of the transmembrane domain Nrg1 mutant mouse model is highly PPI protocol-specific and appears sensitive to the particular conditions of the test laboratory. Our study describes wild type-like PPI under most test conditions and across three different laboratories. The research suggests that analysing one of the alleged hallmarks of animal models for schizophrenia must be done carefully: to obtain reliable PPI data it seems necessary to use more than one particular PPI protocol.
    Behavioural brain research 10/2011; 223(2):336-41. DOI:10.1016/j.bbr.2011.04.051 · 3.39 Impact Factor
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