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Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling
Abstract
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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“Recent studies have revealed anomalies in hippocampal and/or prefrontal PVI in many preclinical animal models aiming to reproduce genetic vulnerabilities (Carlson et al., 2011; Fazzari et al., 2010; Hikida et al., 2007; Wen et al., 2010) or environmental risk factors (Brown, 2011) such as prenatal maternal stress (Stevens et al., 2013), maternal and perinatal immune challenge (Jenkins et al., 2009”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Fazzari et al., 2010
In the citing paper
“Although the expression of ErbB4 is confined to specific types of interneuron in the adult cortex (Fazzari et al., 2010; Neddens and Buonanno, 2010; Vullhorst et al., 2009), ErbB4 is expressed in the majority of cortical interneurons at perinatal stages (Bean et al., 2014).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Fazzari et al., 2010
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- Flames, N. et al. Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1. Neuron 44, 251–261 (2004) · DOI · Paper page
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Metadata
- Authors
- Fazzari, P., Paternain, A. V., Valiente, M., Pla, R., Luján, R., Lloyd, K., Lerma, J., Marín, O., & Rico, B.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- University of Castilla-La Mancha (ES)
- University of California, Davis (US)
- Corresponding author
- Rico, Beatriz
- ORCID
- Venue
- Nature
- Published
- 2010-04
- Volume
- 464
- Issue
- 7293
- Pages
- 1376-1380
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2031755128
- Cited by
- 501
- References
- 42
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 24 · 2023: 28 · 2022: 28 · 2021: 48 · 2020: 23 · 2019: 26 · 2018: 34 · 2017: 29 · 2016: 35 · 2015: 29 · 2014: 39 · 2013: 30 · 2012: 28
- FWCI
- 15.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- neuregulin-1, ErbB4, schizophrenia, GABAergic interneurons, cortical circuit development, axo-axonic synapses, parvalbumin interneurons, chandelier cells, basket cells, synaptic adhesion proteins, neurodevelopmental disorders, neocortex, hippocampus, inhibitory synapse formation, genetic risk factors
- MeSH terms
- Animals, Cell Differentiation, Cerebral Cortex, Dendrites, Embryo, Mammalian, Female, gamma-Aminobutyric Acid, Interneurons, Neural Inhibition, Neural Pathways, Schizophrenia, Synapses, Signal Transduction, Pyramidal Cells, Excitatory Postsynaptic Potentials, Neuregulin-1, Mice, ErbB Receptors, Receptor, ErbB-4, In Vitro Techniques
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