Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci 32: 485-495

Department of Psychiatry and Behavioral Neurosciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Trends in Neurosciences (Impact Factor: 13.56). 09/2009; 32(9):485-95. DOI: 10.1016/j.tins.2009.05.007
Source: PubMed


Schizophrenia (SZ) is primarily an adult psychiatric disorder in which disturbances caused by susceptibility genes and environmental insults during early neurodevelopment initiate neurophysiological changes over a long time course, culminating in the onset of full-blown disease nearly two decades later. Aberrant postnatal brain maturation is an essential mechanism underlying the disease. Currently, symptoms of SZ are treated with anti-psychotic medications that have variable efficacy and severe side effects. There has been much interest in the prodromal phase and the possibility of preventing SZ by interfering with the aberrant postnatal brain maturation associated with this disorder. Thus, it is crucial to understand the mechanisms that underlie the long-term progression to full disease manifestation to identify the best targets and approaches towards this goal. We believe that studies of certain SZ genetic susceptibility factors with neurodevelopmental implications will be key tools in this task. Accumulating evidence suggests that neuregulin-1 (NRG1) and disrupted-in-schizophrenia-1 (DISC1) are probably functionally convergent and play key roles in brain development. We provide an update on the role of these emerging concepts in understanding the complex time course of SZ from early neurodevelopmental disturbances to later onset and suggest ways of testing these in the future.

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    • "Major mental disorders are disorders of brain development (Insel, 2011; Jaaro-Peled et al., 2009). Astrocyte models with manipulation in astrocytic genes at different stages of neurodevelopment (including postnatal period) are likely to be most relevant to psychiatric disorders. "
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    • "The functional NRG1 receptor v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) is expressed in the midbrain dopaminergic neurons in mice and primates (Abe et al., 2009; Zheng et al., 2009). Furthermore, the signaling of NRG1 and its receptor ErbB4 has been implicated in important neurodevelopmental processes of putative relevance to the aetiopathology of schizophrenia (Corfas et al., 2004; Fazzari et al., 2010; Hahn et al., 2006; Jaaro-Peled et al., 2009; Mei and Xiong, 2008). Both the catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) genes are also regulated by hypoxia (Schmidt- Kastner et al., 2006), and are associated with the dopamine system in the brain; COMT is an enzyme involved in the degradation of dopamine and BDNF is one of the trophic factors involved in the development of dopaminergic neurons (Baquet et al., 2005). "
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    ABSTRACT: Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia.
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    • "Such an interaction with Neuregulin-1 has been proposed, for example, for disrupted in schizophrenia 1 (DISC1). Moreover, both NRG1 and DISC1 interact with growth factor receptor-bound protein 2 (Grb2), an adaptor protein located in the postsynaptic densities (Jaaro-Peled et al. 2009). Moreover, NRG1 has been shown to induce phosphorylation of Akt (Guo et al. 2010). "
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    ABSTRACT: Changes in fiber tract architecture have gained attention as a potentially important aspect of schizophrenia neuropathology. Although the exact pathogenesis of these abnormalities yet remains to be elucidated, a genetic component is highly likely. Neuregulin-1 (NRG1) is one of the best-validated schizophrenia susceptibility genes. We here report the impact of the Neuregulin-1 rs35753505 variant on white matter structure in healthy young individuals with no family history of psychosis. We compared fractional anisotropy in 54 subjects that were either homozygous for the risk C allele carriers (n = 31) for rs35753505 or homozygous for the T allele (n = 23) using diffusion tensor imaging with 3T. Tract-Based Spatial Statistics (TBSS), a method especially developed for diffusion data analysis, was used to improve white matter registration and to focus the statistical analysis to major fiber tracts. Statistical analysis showed that homozygous risk C allele carriers featured elevated fractional anisotropy (FA) in the right perihippocampal region and the white matter proximate to the left area 4p as well as the right hemisphere of the cerebellum. We found three clusters of reduced FA values in homozygous C allele carriers: in the left superior parietal region, the right prefrontal white matter and in the deep white matter of the left frontal lobe. Our results highlight the importance of Neuregulin-1 for structural connectivity of the right medial temporal lobe. This finding is in line with well known neuropathological findings in this region in patients with schizophrenia.
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