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Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks

The neuregulin 1 (NRG1) ErbB4 module is at the core of an “at risk” signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-sp...

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Detalles Bibliográficos
Autores principales: Götze, Tilmann, Soto-Bernardini, Maria Clara, Zhang, Mingyue, Mießner, Hendrik, Linhoff, Lisa, Brzózka, Magdalena M, Velanac, Viktorija, Dullin, Christian, Ramos-Gomes, Fernanda, Peng, Maja, Husseini, Hümeyra, Schifferdecker, Eva, Fledrich, Robert, Sereda, Michael W, Willig, Katrin, Alves, Frauke, Rossner, Moritz J, Nave, Klaus-Armin, Zhang, Weiqi, Schwab, Markus H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379540/
https://www.ncbi.nlm.nih.gov/pubmed/33871014
http://dx.doi.org/10.1093/schbul/sbab027
Descripción
Sumario:The neuregulin 1 (NRG1) ErbB4 module is at the core of an “at risk” signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-specific NRG1-ErbB4 hyperactivity for disease-relevant brain endophenotypes. To address these spatiotemporal aspects, we generated transgenic mice for Cre recombinase-mediated overexpression of cystein-rich domain (CRD) NRG1, the most prominent NRG1 isoform in the brain. A comparison of “brain-wide” vs cell type-specific CRD-NRG1 overexpressing mice revealed that pathogenic CRD-NRG1 signals for ventricular enlargement and neuroinflammation originate outside glutamatergic neurons and suggests a subcortical function of CRD-NRG1 in the control of body weight. Embryonic onset of CRD-NRG1 in glutamatergic cortical networks resulted in reduced inhibitory neurotransmission and locomotor hyperactivity. Our findings identify ventricular enlargement and locomotor hyperactivity, 2 main endophenotypes of schizophrenia, as specific consequences of spatiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling.