title: Disruption of the ErbB signaling in adolescence increases striatal dopamine levels and affects learning and hedonic-like behavior in the adult mouse.
abstract: The ErbB signaling pathway has been genetically and functionally implicated in schizophrenia. Numerous findings support the dysregulation of Neuregulin (NRG) and epidermal growth factor (EGF) signaling in schizophrenia. However, it is unclear whether alterations of these pathways in the adult brain or during development are involved in the pathophysiology of schizophrenia. Herein we characterized the behavioral profile and molecular changes resulting from pharmacologically blocking the ErbB signaling pathway during a critical period in the development of decision making, planning, judgments, emotions, social cognition and cognitive skills, namely adolescence. We demonstrate that chronic administration of the pan-ErbB kinase inhibitor JNJ-28871063 (JNJ) to adolescent mice elevated striatal dopamine levels and reduced preference for sucrose without affecting locomotor activity and exploratory behavior. In adulthood, adolescent JNJ-treated mice continue to consume less sucrose and needed significantly more correct-response trials to reach the learning criterion during the discrimination phase of the T-maze reversal learning task than their saline-injected controls. In addition, JNJ mice exhibited deficit in reference memory but not in working memory as measured in the radial arm maze. Inhibition of the pathway during adolescence did not affect exploratory behavior and locomotor activity in the open field, social interaction, social memory, and reversal learning in adult mice. Our data suggest that alteration of ErbB signaling during adolescence resulted in changes in the dopaminergic systems that emerge in pathological learning and hedonic behavior in adulthood, and pinpoints the possible role of the pathway in the development of cognitive skills and motivated behavior.
authors.affiliation: Department of Biotechnology Engineering, ORT Braude College, Karmiel, Israel.
authors.forename: Idit
authors.initials: I
authors.lastname: Golani
authors.affiliation: Psychobiology Research Laboratory, Mazra Mental Health Center, Akko, Israel; Faculty of Medicine in the Galilee, Bar-Ilan University, Zefat, Israel.
authors.forename: Hagar
authors.initials: H
authors.lastname: Tadmor
authors.affiliation: Section on Molecular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Buonanno
authors.affiliation: Psychobiology Research Laboratory, Mazra Mental Health Center, Akko, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Kremer
authors.affiliation: Psychobiology Research Laboratory, Mazra Mental Health Center, Akko, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. Electronic address: alons@mazra.health.gov.il.
authors.forename: Alon
authors.initials: A
authors.lastname: Shamir
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: C526582:JNJ 28871063; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D066246:ErbB Receptors; D004298:Dopamine
keywords: Animal behavior; Cognition; Dopaminergic system; ErbB receptor; Neuregulin; Schizophrenia