title: Prenatal stress down-regulates Reelin expression by methylation of its promoter and induces adult behavioral impairments in rats.
abstract: Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination and synaptic maturation, and its deregulation has been associated with maladaptive conditions. In the present study, we address the effect of prenatal restraint stress (PNS) upon Reelin expression and signaling in pregnant rats during the last 10 days of pregnancy. Animals from one group, including control and PNS exposed fetuses, were sacrificed and analyzed using immunohistochemical, biochemical, cell biology and molecular biology approaches. We scored changes in the expression of Reelin, its signaling pathway and in the methylation of its promoter. A second group included control and PNS exposed animals maintained until young adulthood for behavioral studies. Using the optical dissector, we show decreased numbers of Reelin-positive neurons in cortical layer I of PNS exposed animals. In addition, neurons from PNS exposed animals display decreased Reelin expression that is paralleled by changes in components of the Reelin-signaling cascade, both in vivo and in vitro. Furthermore, PNS induced changes in the DNA methylation levels of the Reelin promoter in culture and in histological samples. PNS adult rats display excessive spontaneous locomotor activity, high anxiety levels and problems of learning and memory consolidation. No significant visuo-spatial memory impairment was detected on the Morris water maze. These results highlight the effects of prenatal stress on the Cajal-Retzius neuronal population, and the persistence of behavioral consequences using this treatment in adults, thereby supporting a relevant role of PNS in the genesis of neuropsychiatric diseases. We also propose an in vitro model that can yield new insights on the molecular mechanisms behind the effects of prenatal stress.
authors: Departamento de Psiquiatría, Escuela de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Católica de Chile, Santiago, Chile; Laboratory of Cell and Neuronal Dynamics (Cenedyn), Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors: Ismael
authors: I
authors: Palacios-García
authors: Departamento de Psiquiatría, Escuela de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Ariel
authors: A
authors: Lara-Vásquez
authors: Centro de Investigación Biomédica, Facultad de Medicina, Universidad Diego Portales, Santiago, Chile.
authors: Juan F
authors: JF
authors: Montiel
authors: Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile.
authors: Gabriela F
authors: GF
authors: Díaz-Véliz
authors: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, and Fondo de Áreas Prioritarias (FONDAP) "Center for Genome Regulation", Universidad Andrés Bello, Santiago, Chile.
authors: Hugo
authors: H
authors: Sepúlveda
authors: Laboratory of Cell and Neuronal Dynamics (Cenedyn), Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors: Elías
authors: E
authors: Utreras
authors: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, and Fondo de Áreas Prioritarias (FONDAP) "Center for Genome Regulation", Universidad Andrés Bello, Santiago, Chile.
authors: Martín
authors: M
authors: Montecino
authors: Laboratory of Cell and Neuronal Dynamics (Cenedyn), Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors: Christian
authors: C
authors: González-Billault
authors: Departamento de Psiquiatría, Escuela de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Francisco
authors: F
authors: Aboitiz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018811:Maternal Exposure; D001523:Mental Disorders / Q000209:etiology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011401:Promoter Regions, Genetic; D051381:Rats; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D013315:Stress, Psychological
chemical_list: D034961:Antigens, Nuclear; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; C546339:Rbfox3 protein, rat; D000091042:Reelin Protein; C000717129:Reln protein, rat; D051360:Cyclin-Dependent Kinase 5; D012697:Serine Endopeptidases