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.
Highlights
Stress in early life has been proposed as a main cause of neuropsychiatric diseases such as depression, schizophrenia and bipolar disorders [1,2,3]
We observed that the average adrenal gland weight was 25% higher in stressed rats compared to controls (p
We evaluated the effect of PNS on perinatal expression (E20) of the Reelin protein in the rat cerebral cortex
Summary
Stress in early life has been proposed as a main cause of neuropsychiatric diseases such as depression, schizophrenia and bipolar disorders [1,2,3]. Application of stress protocols to pregnant animals increases the release of stress-related hormones such as cortisol, which in turn induces higher than normal cortisol concentrations in embryos, which may affect the expression of other factors and in general, development and growth [4,5,6,7]. Animal models of prenatal stress usually include exogenous administration of glucocorticoids and restraint of pregnant dams. Regardless of the chosen method to induce prenatal stress, newborn and adult rodents display several abnormalities such as decreased number and complexity of dendritic spines in the hippocampus [8], decreased expression of mineralocorticoid receptors [9], and global changes in DNA methylation including gene promoters [10]. Prenatal stress has been associated with anxious behavior [11, 12], decrease in synaptic plasticity [13], and impairments in learning and memory [12, 14, 15], all of which are conditions that support etiological relationships between prenatal stress and some neuropsychiatric diseases
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