Cognition- and Anxiety-Related Behavior, Synaptophysin and MAP2 Immunoreactivity in the Adult Rat Treated with a Single Course of Antenatal Betamethasone

Abstract

ABSTRACT:We investigated the effects of a single course of antenatal betamethasone on cognition-and anxiety-related behavior and synaptophysin and microtubule-associated protein 2 (MAP2) immunoreactivity in the adult rat hippocampus. On d 20 of gestation, pregnant rats were injected with either 1) 170 g/kg body weight of betamethasone ("clinically equivalent dose," equivalent to 12 mg twice, 24 h apart); 2) half this dose; or 3) vehicle. Cognition-and anxiety-related behavior of the offspring was analyzed at an age of 5 mo using the Morris water maze, object recognition task, and open field test. Subsequently, synaptophysin and MAP2 immunoreactivity were measured in the hippocampus. We report no detrimental effects of antenatal betamethasone on cognition-and anxiety-related behavior and synaptophysin immunoreactivity in the adult rat. On the other hand, MAP2 immunoreactivity was decreased by betamethasone in males, suggesting a permanent impairment in the hippocampus. Interestingly, the lower dose appears to have less influence in terms of growth restriction, known to be associated with an increased risk of disease in adulthood. Further research might elucidate whether the betamethasone effect on hippocampal neurons persists later in life and could affect the aging process increasing the risk for neuropathology of the adult. A ntenatal glucocorticoids are widely used to prevent respiratory distress syndrome in case of threat of preterm delivery (1). Although beneficial for lung maturation, this treatment causes a wide range of side effects in humans, including a reduction in weight and head circumference at birth (2), and in impairment in both circulating glucocorticoid bioactivity (3) and cortisol response to stressors (4). Animal studies showed that antenatal glucocorticoids affect the hypothalamic-pituitary-adrenal (HPA) axis (5), an impairment of which has been linked to the development of anxiety and mood disorders (6). Further, this treatment has been reported to reduce DNA content (7), cell proliferation rate (8), synaptic density (9), and neurotrophic factor concentrations within the neonatal brain (10) and induces neural degeneration within the developing hippocampus (11). However, little is known about the consequences for later life, in particular, the effects on cognition-and anxiety-related behavior are unclear (5,12).The presynaptic marker protein synaptophysin is a calciumbinding protein that plays an important role in the generation and maintenance of small vesicle membranes and their interaction with cytoskeletal elements. Decrease in the synaptophysin IR is associated with brain injury and aging, possibly reflecting functional disturbances of synaptic transmission (13). The neuronal MAP2 determines stability and arrangement of neuronal microtubules. Loss of MAP2 IR after brain injury correlates with neuronal degeneration (14) and is associated with age-related impairment of synaptic plasticity, cognition, and memory functions. Interestingly, both synaptophysin IR and MAP2 IR have been reported ...

Antenatal betamethasone produces protracted changes in anxiety‐like behaviors and in the expression of microtubule‐associated protein 2, brain‐derived neurotrophic factor and the tyrosine kinase B receptor in the rat cerebellar cortex

“…Additionally, the fact that anxious behaviors in the MB test were detected at the early post‐weaning age (P22) suggests that this test may be more sensitive to detecting anxiety‐like states in rodents compared with the EPM. On the contrary, Bruschettini et al (2006) using a similar animal model report no harmful effects of prenatal BET administration (a single course of BET, 170 μg kg −1 ) on anxiety‐like behavior. This discrepancy could be explained by differences in the tests used (open field versus EPM/MB employed in the current study) and the animals' age analyzed (P150 versus P22/52/82).…”

“…Similarly, studies carried out in sheep demonstrated that prenatal BET produced significant decreases in the brain cytoskeletal microtubule‐associated proteins (MAPs) and the presynaptic marker protein synaptophysin (Antonow‐Schlorke et al, 2003). Considering that Purkinje cell dendritic outgrowth and maintenance depends in part on the expression of the cytoskeletal microtubule associated protein 2 (MAP2; Goodlett et al, 1990; Teng et al, 2001; Tucker et al, 1988), the first objective of the present study was to determine whether prenatal betamethasone administration (170 μg kg −1 , twice during gestational day 20, G20; Bruschettini et al, 2006; Scheepens et al, 2003) alters the immunohistochemical expression of MAP2 at three relevant postnatal stages, i.e., the post‐weaning (P22), adolescence (P52) and young adult (P82) stages in rats. Also, since brain‐derived neurotrophic factor (BDNF) significantly contributes to Purkinje cell differentiation, the second objective was to assess the deleterious impact of prenatal BET administration on BDNF and its high‐affinity tyrosine kinase B (TrkB) receptor expression (Goodlett et al, 1990; Tucker et al, 1988).…”

Effects of a Single Course of Prenatal Betamethasone on Dendritic Development in Dentate Gyrus Granular Neurons and on Spatial Memory in Rat Offspring

“…We used this procedure because it is equivalent to that employed in the obstetrical clinic (two doses every 24 hours, 12 mg per dose). 8 Day G20 was chosen because it corresponds to the approximate ontogenetic stage of a human preterm fetus (24-32 weeks' gestation). CON group received an equal volume (1 mL) of normal saline.…”

“…Considering that various studies have reported that antenatal exposure to sGC decreases postnatal weight, 8,15 we measured the body and brain weights of the animals at birth (P0), "infancy" (P22), and "adolescence" (P52).…”

“…For instance, some studies showed that a single course of antenatal betamethasone alters the cognition and microtubule-associated protein 2 (MAP-2) immunoreactivity in the hippocampus of adult rats. 8 In addition, Noorlander et al showed that prenatal dexamethasone treatment decreased hippocampal cell proliferation in the dentate gyrus as well as impairing performance in the Morris water maze in adult mice. 9 The vulnerability of the hippocampus to high levels of antenatal corticosteroids may be explained by the fact that this area expresses very high levels of both GC and mineralocorticoid receptors not only in adulthood 10 but also during fetal development.…”