Repeated restraint stress and corticosterone injections during late pregnancy alter GAP‐43 expression in the hippocampus and prefrontal cortex of rat pups

Abstract

In the offspring of prenatal stress animals, overactivity and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal axis are consistent finding. However, little was known about how prenatal stress can permanently alter developmental trajectories of pup's brain. Growth-associated protein-43 (GAP-43) is a presynaptic membrane phosphoprotein whose expression increases during developmental events such as axonal outgrowth or remodeling and synaptogenesis. Phosphorylation of GAP-43 by protein kinase C was correlated with enhanced axonal growth and transmitter release. In adult animals, increase of GAP-43 correlated with monoaminergic deficit in neuropsychiatric disorders. The present study examines the effects of repeated maternal restraint stress on the level of GAP-43 in the brain of rat pups. The results showed that prenatal stress significantly increased GAP-43 level in the PFC of rat pup during PND 7-14 as compared to control but not significant difference when observed at PND 21. Increased GAP-43 expression was also observed in the pup's hippocampus during the same postnatal periods. However, when observed at PND 60, pups born from stressed mother showed a significant lower (p<0.001) GAP-43 expression as compare with control group. These changes indicate the direct effect of corticosteroid hormone, since repeated maternal injection with corticosterone (CORT, 40 mg/kg) during GD 14-21 also gave the same results. PND 7-14 is the peak period of synaptogenesis in these brain areas and abnormal axon sprouting and reorganization may lead to a defect in synaptic pruning at later stage of life. The results suggested that maternal stress is harmful to the developing brain and upregulation of GAP-43 indicated a protective mechanism against the toxicity of maternal stress hormone. Prenatal stress alter the normal developmental trajectories in the pup's brain may underlies the mechanism link between early life stress and neuropsychopathology in later life.

Effects of prenatal exposure to silver nanoparticles on spatial cognition and hippocampal neurodevelopment in rats

“…This demonstrated that GAP-43 expression was sensitive to prenatal stress. Change of GAP-43 expression by prenatal stress was also observed in other studies (Jutapakdeegul et al, 2010;Neeley et al, 2011). GAP-43 has been termed a "growth" or "plasticity" protein and is considered a crucial component of the axon and presynaptic terminal (Strittmatter et al, 1995;Benowitz and Routtenberg, 1997).…”

Early Life Programming of Obesity: The Impact of the Perinatal Environment on the Development of Obesity and Metabolic Dysfunction in the Offspring.

“…Prenatal stress, such as may be associated with severe famine situations, can lead to permanent changes in HPA axis function, including exacerbated synaptic pruning in regions associated with the HPA axis [225] as well as changes in GR and MR [181,226] and altered glucocorticoid responses to stress [182,227,228]. This altered sensitivity of the HPA axis could potentially lead to changes in glucocorticoid-mediated appetite regulation and energy storage.…”

The glucocorticoid contribution to obesity

“…Prenatal stress can interfere with synaptic pruning during brain development in regions that are important for HPA axis control, the prefrontal cortex (Spencer et al 2005) and hippocampus (Jacobson and Sapolsky 1991). In particular, it has recently been determined that growth-associated protein of 43 kDa (GAP-43), an intracellular protein involved in the establishment and reorganization of synaptic connections during development (Pfenninger et al 1991;Larsson 2006), is up-regulated in the second week after birth and reduced in adulthood in offspring from restraint-stressed dams (Jutapakdeegul et al 2010). These findings indicate that prenatal stress can produce lasting changes in the connectivity of these regions, potentially affecting HPA axis sensitivity in the long term.…”