title: Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior.
abstract: Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.
authors.affiliation: Departamento de Psiquiatría, Escuela de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Negrón-Oyarzo
authors.affiliation: Departamento de Psiquiatría, Escuela de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ariel
authors.initials: A
authors.lastname: Lara-Vásquez
authors.affiliation: Departamento de Psiquiatría, Escuela de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ismael
authors.initials: I
authors.lastname: Palacios-García
authors.affiliation: Departamento de Psiquiatría, Escuela de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Católica de Chile, Santiago, Chile. pfuentealba@uc.cl.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentealba
authors.affiliation: Departamento de Psiquiatría, Escuela de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Católica de Chile, Santiago, Chile. faboitiz@puc.cl.
authors.forename: Francisco
authors.initials: F
authors.lastname: Aboitiz
mesh_terms: D001921:Brain / Q000196:embryology* / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D003072:Cognition Disorders / Q000503:physiopathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D000091042:Reelin Protein; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology* / Q000503:physiopathology*; D012697:Serine Endopeptidases / Q000235:genetics*; D012920:Social Behavior Disorders / Q000503:physiopathology; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; D012697:Serine Endopeptidases
keywords: DNA methylation; Functional connectivity; Prefrontal cortex; Prenatal stress; Reelin; Schizophrenia