Maternal stress induces long-lasting Purkinje cell developmental impairments in mouse offspring

Abstract

A number of clinical studies suggest that prenatal stress can be a risk factor in the development of various psychopathologies, including schizophrenia, depression, anxiety, and autism. The cerebellar vermis has been shown to be involved in most of these disorders. In the present study, therefore, we evaluate the effect of maternal stress on long-term alterations in vermal Purkinje cell morphology. Furthermore, to discern whether these structural changes are associated with anxious behavior, the exploratory drive in the elevated plus maze was evaluated. Pregnant CF-1 mice were randomly assigned to control (n = 14) or stressed (n = 16) groups. Dams of the stressed group were subjected to restraint stress between gestational days 14 and 20, while control pregnant dams remained undisturbed in their home cages. Anxious behavior and Purkinje cell morphology were evaluated in three ontogenetic stages: postweaning, adolescence, and adulthood. Although exploratory behavior in the elevated plus maze was unaffected by prenatal stress, the Purkinje cell morphology showed a transient period of abnormal growth (at postweaning and juvenile stages) followed by dramatic dendritic atrophy in adulthood. In conclusion, prenatal stress induced significant long-lasting bimodal changes in the morphology of vermal Purkinje cells. These structural alterations, however, were not accompanied by anxious behaviors in the elevated plus maze.

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

“…We found that rats prenatally treated with betamethasone at G20 showed a significant reduction in the immunohistochemical expression of MAP2 and BDNF together with increases in the expression of the TrkB receptor. Consistent with our previous Golgi morphological data (Pascual et al, 2010, 2014), the observed molecular changes reached significance later in life, i.e., during the adolescent or young adult stages. Of note, the data presented in this report emphasize the immunohistochemical localization of cytoskeletal, secreted and receptor complex proteins and do not reflect quantitative expression.…”

“…Furthermore, in a recent study, we demonstrated that the prenatal administration of the synthetic glucocorticoid betamethasone (BET) alters the expression of the neuroprotective calcium binding protein calbinbin‐D28k in vermal Purkinje cells (Pascual et al, 2014), suggesting that prenatal GCs make cerebellar tissue more vulnerable to further ontogenetic impairments. In those studies, morphological, molecular and behavioral changes occurred when the animals reached adolescence or young adulthood instead of during early postnatal life, which indicates a protracted effect of endogenous (Pascual et al, 2010) or exogenous (Pascual et al, 2014) GCs. 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).…”

“…Another brain region that appears to be highly vulnerable to prenatal stress and glucocorticoid administration is the cerebellum, particularly the medial portion or vermis. Previous studies demonstrated that animals that experience prenatal stress exhibit a significant reduction in Purkinje cell dendritic outgrowth (Pascual et al, 2010) and the synapse‐to‐neuron ratio (Ulupinar and Yucel, 2005). Furthermore, in a recent study, we demonstrated that the prenatal administration of the synthetic glucocorticoid betamethasone (BET) alters the expression of the neuroprotective calcium binding protein calbinbin‐D28k in vermal Purkinje cells (Pascual et al, 2014), suggesting that prenatal GCs make cerebellar tissue more vulnerable to further ontogenetic impairments.…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…Furthermore, maternal stress significantly altered cerebellar Purkinje cell development in mice (Pascual et al 2010), which is known to be dependent upon reelin expression in both males and female mice (Maloku et al 2010). These discrepancies may be due to strain effects, indeed alterations in brain-derived neurotrophic factor (BDNF), glucocorticoid receptors and nicotinic receptor expression in the hippocampus following prenatal stress in rats are highly dependent on background strain (Neeley et al 2011).…”

Above genetics: Lessons from cerebral development in autism

“…Wolf et al [117] have found in vitro that when exposing murine hippocampal neural stem cells to high levels of glucocorticoid, neurogenesis halts and a greater proportion of cells undergo apoptosis; yet with exposure to low levels of glucocorticoid, an increase in progenitor proliferation occurs. Aside from local production of glucocorticoid, maternal levels can also have a critical effect on embryonic development, and so maternal infections and antenatal stress have received increasing attention over the years in the investigation of maternal-fetal interactions [118, 119]. In conclusion, a given immune response may not only be shaped by an invading antigen, it can be shaped by past infection, guided by the endocrine system, and even altered by mood and stress levels.…”