| Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. | |
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MedLine Citation:
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PMID: 20393464 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Schizophrenia is a complex disorder that interferes with the function of several brain systems required for cognition and normal social behaviour. Although the most notable clinical aspects of the disease only become apparent during late adolescence or early adulthood, many lines of evidence suggest that schizophrenia is a neurodevelopmental disorder with a strong genetic component. Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia, although their precise role in the disease process remains unknown. Here we show that Nrg1 and ErbB4 signalling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA (gamma-aminobutyric acid)-containing interneurons. In contrast to the prevalent view, which supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, we found that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrate that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Altogether, our results indicate that Nrg1 and ErbB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes in the aetiology of schizophrenia. |
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Authors:
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Pietro Fazzari; Ana V Paternain; Manuel Valiente; Ramón Pla; Rafael Luján; Kent Lloyd; Juan Lerma; Oscar Marín; Beatriz Rico |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-04-14 |
Journal Detail:
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Title: Nature Volume: 464 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-29 Completed Date: 2010-06-15 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 1376-80 Citation Subset: IM |
Affiliation:
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Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Differentiation Cerebral Cortex / cytology, embryology, growth & development, metabolism* Dendrites / metabolism Embryo, Mammalian Excitatory Postsynaptic Potentials / genetics, physiology Female Interneurons / metabolism* Mice Neural Inhibition / genetics, physiology Neural Pathways / physiology* Neuregulin-1 / metabolism* Pyramidal Cells / metabolism Receptor, Epidermal Growth Factor / deficiency, genetics, metabolism* Schizophrenia / genetics, metabolism Signal Transduction* Synapses / metabolism gamma-Aminobutyric Acid / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Neuregulin-1; 0/Nrg1 protein, mouse; 56-12-2/gamma-Aminobutyric Acid; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.10.1/receptor tyrosine-protein kinase erbB-4 |
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