Abstract
The susceptibility genes for schizophrenia Neuregulin-1 (NRG1) and ErbB4 have critical functions during brain development and in the adult. Alterations in the ErbB4 signaling pathway cause a variety of neurodevelopmental defects including deficiencies in neuronal migration, synaptic plasticity, and myelination. I have used the ErbB4-/- HER4heart KO mice to study the neurodevelopmental insults associated to deficiencies in the NRG1-ErbB4 signaling pathway and their potential implication with brain disorders such as schizophrenia, a chronic psychiatric disease affecting 1% of the population worldwide. ErbB4 deletion results in an array of neurodevelopmental deficits that are consistent with a schizophrenic model. First, similar defects appear in multiple brain structures, from the cortex to the cerebellum. Second, these defects affect multiple aspects of brain development, from deficits in neuronal migration to impairments in excitatory/inhibitory systems, including reductions in brain volume, cortical and cerebellar heterotopias, alterations in number and distribution of specific subpopulations of interneurons, deficiencies in the astrocytic and oligodendrocytic lineages, and additional insults in major brain structures. This suggests that alterations in specific neurodevelopmental genes that play similar functions in multiple neuroanatomical structures might account for some of the symptomatology observed in schizophrenic patients, such as defects in cognition. ErbB4 mutation uncovers flaws in brain development that are compatible with a neurodevelopmental model of schizophrenia, and it establishes a comprehensive model to study the basis of the disorder before symptoms are detected in the adult.
Highlights
Brain development is a tightly regulated process wherein multiple signaling pathways cooperate to establish an intricate neuronal network that connects different structures in the central nervous system (CNS)
NRG1 functions are largely mediated by a class of receptor tyrosine kinases (ErbB14) (Yarden and Sliwkowski, 2001; Falls, 2003), and through their activation regulate: radial glia formation and survival (Adlkofer and Lai, 2000), oligodendrocyte formation and axon myelination (Canoll et al, 1996; Fernandez et al, 2000; Schmucker et al, 2003), axon pathfinding (Lopez-Bendito et al, 2006), neuronal migration (Anton et al, 1997; Rio et al, 1997; Flames et al, 2004; Li et al, 2012), expression of neurotransmitter receptors (Ozaki et al, 1997; Rieff et al, 1999; Liu et al, 2001) and dendritic development (Rieff and Corfas, 2006)
The detailed neuroanatomical description of this study differs from that assumption and, offers clear evidence that the cortical thickness in the KO is reduced at P7 by 25% and in the adult by 6%, with a reduction in brain volume in the adult KO by 15%. (0.85 ± 0.02, p = 0.0027∗∗∗)
Summary
Brain development is a tightly regulated process wherein multiple signaling pathways cooperate to establish an intricate neuronal network that connects different structures in the central nervous system (CNS). Schizophrenia is a complex neurological disorder that affects multiple neuroanatomical structures and has a strong developmental component (Harrison, 1999; Walsh et al, 2008; Muraki and Tanigaki, 2015). It is not caused by defects in a single gene, but rather is a multigenic. Understanding neurodevelopmental insults that might lead to schizophrenia is a critical step to conceptualize the driving factors that might cause the disease
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