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: 1.52). 03/2005; 16(3):271-5. DOI: 10.1097/00001756-200502280-00014
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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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    • "Schizophrenia patients exhibit elevated levels of functional NRG1 protein (consistent with increased BACE1 levels), and chronic antipsychotic treatment decreases NRG1 signaling and expression (Pan et al. 2011). Despite this apparent contradiction, BACE1 −/− and NRG1 −/− both exhibit schizophreniform behaviors including impaired latent inhibition (Rimer et al. 2005), social behavior (Deakin et al. 2009; Kato et al. 2010) and paired pulse inhibition (Deakin et al. 2009; Kato et al. 2010; Savonenko et al. 2008). However, these cognitive and negative symptoms are "
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    ABSTRACT: β-Site APP-cleaving Enzyme 1 (BACE1) is a protease that has been linked to schizophrenia, a severe mental illness that is potentially characterized by enhanced dopamine release in the striatum. Here we used acute amphetamine administration to stimulate neuronal activity and investigate the neurophysiological and locomotor-activity response in BACE1-deficient (BACE1(-/-) ) mice. We measured locomotor activity at baseline and after treatment with amphetamine (3.2 and 10 mg/kg). While baseline locomotor activity did not vary between groups, BACE1(-/-) mice exhibited reduced sensitivity to the locomotor-enhancing effects of amphetamine. Using high-performance liquid chromatography to measure dopamine and dopamine metabolites in the striatum, we found no significant differences in BACE1(-/-) compared to wild-type mice. To determine if dopamine neuron excitability is altered in BACE1(-/-) mice we performed patch-clamp electrophysiology in putative dopamine neurons from brain slices that contained the substantia nigra. Pacemaker firing rate was slightly increased in slices from BACE1(-/-) mice. We next measured G protein-coupled potassium currents produced by activation of D2 autoreceptors, which strongly inhibit firing of these neurons. The maximal amplitude and decay times of D2 autoreceptor currents were not altered in BACE1(-/-) mice, indicating no change in D2 autoreceptor-sensitivity and dopamine transporter-mediated reuptake. However, amphetamine (30 μM)-induced potassium currents produced by efflux of dopamine were enhanced in BACE1(-/-) mice, perhaps indicating increased vesicular dopamine content in the midbrain. This suggests a plausible mechanism to explain the decreased sensitivity to amphetamine-induced locomotion, and provides evidence that decreased availability of BACE1 can produce persistent adaptations in the dopaminergic system. This article is protected by copyright. All rights reserved.
    Genes Brain and Behavior 04/2015; 14(5). DOI:10.1111/gbb.12222 · 3.66 Impact Factor
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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 06/2014; 211:79-112. DOI:10.1016/B978-0-444-63425-2.00004-0 · 2.83 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 · 3.92 Impact Factor
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