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

Goetze, Tilmann; Soto-Bernardini, Maria Clara; Zhang, Mingyue; Miessner, Hendrik; Linhoff, Lisa; Brzozka, Magdalena M.; Velanac, Viktorija; Dullin, Christian; Ramos-Gomes, Fernanda; Peng, Maja; Husseini, Humeyra; Schifferdecker, Eva; Fledrich, Robert; Sereda, Michael W.; Willig, Katrin; Alves, Frauke; Rossner, Moritz J.; Nave, Klaus-Armin; Zhang, Weiqi und Schwab, Markus H. (2021): Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks. In: Schizophrenia Bulletin, Bd. 47, Nr. 5: S. 1409-1420

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 typespecific 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 spa tiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0586-7614
• Sprache: Englisch