Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice, Neuroreport 20, 1523-1528

Department of Psychiatry, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Neuroreport (Impact Factor: 1.52). 11/2009; 20(17):1523-8. DOI: 10.1097/WNR.0b013e328330f6e7
Source: PubMed


Neuregulin 1 (NRG1) is a pleiotropic growth factor involved in diverse aspects of brain development and function. In schizophrenia, expression of the NRG1 type I isoform is selectively increased. However, virtually nothing is known about the roles of this isoform in brain. We have studied transgenic mice overexpressing type I NRG1(NRG1type 1-tg) using a series of behavioural tests. NRG1(type 1-tg) mice have a tremor, are impaired on the accelerating rotarod, and have reduced prepulse inhibition in the context of an increased baseline startle response. There is no overall anxiety or activity phenotype, although female NRG(1type 1-tg) mice show mild increases in anxiety on some measures. The pattern of results shows both similarities and differences to those reported in hypomorphic NRG1 mice, and may be relevant for interpreting the increased NRG1 type I expression observed in schizophrenia.

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Available from: Amanda Law, Jul 23, 2014
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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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    • "The basic behavioral data reported in the present study, along with data regarding the basic behavioral phenotypes that have been reported for different lines of Nrg1-related mutant mice, are summarized in Table 3. There are several inconsistencies in this dataset; for example, PPI deficits have been observed in studies of type III Nrg1 mutant mice (Chen et al., 2008), ErbB4 mutant mice (Shamir et al., 2012), ErbB2/4 mutant mice (Barros et al., 2009), and NRG1-overexpressing transgenic mice (Deakin et al., 2009; Kato et al., 2010), and in some (but not all) studies of the original TMc-Nrg1 mutant mice (Stefansson et al., 2002; Desbonnet et al., 2012). These original TMc-Nrg1+/− mutant mice have been widely used in recent years. "
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    ABSTRACT: Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males.
    Frontiers in Behavioral Neuroscience 04/2014; 8:126. DOI:10.3389/fnbeh.2014.00126 · 3.27 Impact Factor
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    • "This supports findings recently published by the group of Matthew (Davies et al., 2012) demonstrating that the genomewide variety between promoter methylation variance across tissues is less than expected. Additionally, nonparametric correlation analysis revealed a highly significant correlation between blood and PFC (r = 0.195, p b 0.001) as well as with averaged PPI measurements (r = 0.308, p b 0.001), thereby reaffirming the hypothesis of NRG1 overexpression contributing to the schizophrenia phenotype (Deakin et al., 2009). We also observed a weak correlation of blood and dHIP methylation (r = 0.025, p = 0.025) which may be neglected due to its weak coefficient (Supplementary Table S5). "
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    ABSTRACT: Low prepulse inhibition (PPI) of startle is associated with reduced sensorimotor gating found in schizophrenia. In rats with breeding-induced low PPI neuregulin (NRG1) methylation was significantly decreased in brain regions associated with this phenotype and with schizophrenia, i.e., the medial prefrontal cortex, the nucleus accumbens, and the ventral hippocampus, while methylation in the amygdala and dorsal hippocampus was less affected. The dopamine D2 receptor (DRD2) promoter region showed negligible changes between groups. Rats with low PPI may be used to understand the reduced epigenetic regulation found in schizophrenia, and eventually lead to the development of novel therapies.
    Schizophrenia Research 07/2013; 150(1). DOI:10.1016/j.schres.2013.07.012 · 3.92 Impact Factor
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