Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks. (19th April 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Schizophrenia bulletin. Volume 47:Number 5(2021)
• Page Start: 1409
• Page End: 1420
• Publication Date: 2021-04-19
• Subjects: schizophrenia -- conditional transgenic mice -- ErbB4 receptor -- ventricular enlargement; Schizophrenia -- Periodicals; Schizophrenia -- Research -- Periodicals; 616.898005
• DOI: 10.1093/schbul/sbab027
• Languages: English
• ISSNs: 0586-7614

Abstract

Abstract: 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.