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: 12.9). 09/2009; 32(9):485-95. DOI: 10.1016/j.tins.2009.05.007
Source: PubMed

ABSTRACT 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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Available from: Hanna Jaaro-Peled, Aug 25, 2015
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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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    ABSTRACT: Astrocytes regulate multiple processes in the brain ranging from trophic support of developing neurons to modulation of synaptic neurotransmission and neuroinflammation in adulthood. It is, therefore, understandable that pathogenesis and pathophysiology of major psychiatric disorders involve astrocyte dysfunctions. Until recently, there has been the paucity of experimental approaches to studying the roles of astrocytes in behavioral disease. A new generation of in vivo models allows us to advance our understanding of the roles of astrocytes in psychiatric disorders. This review will evaluate the recent studies that focus on the contribution of astrocyte dysfunction to behavioral alterations pertinent to schizophrenia and will propose the possible solutions of the limitations of the existing approaches.
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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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    • "Schizophrenia is a severe mental disorder that affects approximately 1 % of the world's population. Accumulating data suggest that dysregulation of molecules associated with the development of neural circuits might contribute to the pathogenesis of schizophrenia (Mei and Xiong 2008; Jaaro-Peled et al. 2009; Brandon and Sawa 2011; Penzes et al. 2011; Arguello and Gogos 2012). One of the candidate susceptibility genes for schizophrenia that play important roles in neural development is disrupted-in-schizophrenia 1 (DISC1) (Mackie et al. 2007; Brandon and Sawa 2011) which was originally discovered as a putative gene for major psychiatric disorders in a Scottish pedigree (Millar et al. 2000). "
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