Repeated variable prenatal stress alters pre‐ and postsynaptic gene expression in the rat frontal pole

Abstract

Exposure of pregnant women to stress during a critical period of fetal brain development is an environmental risk factor for developing schizophrenia in the adult offspring. We have applied a repeated variable stress paradigm to pregnant Sprague-Dawley rats during the last week of gestation coinciding with the second trimester in human brain development. Here we report our findings from a microarray analysis of the frontal pole of the prenatally stressed adult offspring and non-stressed adult controls complemented with measurement of plasma corticosterone levels following exposure to an acute stress. The direction of change of selected genes was confirmed by real time quantitative fluorescence PCR and in situ hybridization. The analysis revealed significant changes in genes associated with the NMDA receptor/postsynaptic density complex and the vesicle exocytosis machinery including NMDA receptor NR1 and NR2A subunits, densin-180, brain enriched guanylate kinase-associated protein, synaptosomeassociated protein of 25 kDa, synaphin/complexin and vesicle-associated membrane protein 2/synaptobrevin 2. Interestingly, some of the changes in this animal preparation are analogous to changes observed in schizophrenic and bipolar patients. Our results suggest that application of a repeated variable prenatal stress paradigm during a critical period of fetal brain development reprograms the response of the hypothalamo-pituitary-adrenal axis to acute stress and results in gene expression changes that may have enduring effects on synaptic function in the offspring during adulthood.

Prenatal stress does not alter innate novelty-seeking behavioral traits, but differentially affects individual differences in neuroendocrine stress responsivity

“…Such effects are likely related to a host of neuroanatomical changes and gene expression differences related to PS exposure. For example, multiple studies reported that PS reduced GR density in the adult hippocampus (Henry et al, 1994, Maccari et al, 1995, altered neurogenesis in the dentate gyrus (Lemaire et al, 2000), reduced hippocampal weight (Szuran et al, 1994, and induced widespread gene expression changes that reflect possible PS-induced alterations in hippocampal synaptic function (Kinnunen et al, 2003). Our findings suggest that certain individuals (LR pups in our hands) may be particularly susceptible to developing these effects.…”

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

“…In addition, a study in rats has shown increased BEGAIN expression in the frontal pole in response to prenatal stress as a paradigm for the etiology of schizophrenia. 55 . BEGAIN is highly associated to the postsynaptic density proteins, and particularly to the postsynaptic density 95 (PSD95) 34,56,57 , having 90% co-localization with PSD95 56 , and a role in sustaining the structure of this scaffolding protein 58 .…”

Prenatal stress generates deficits in rat social behavior: Reversal by oxytocin

“…Exposure to an unpredictable prenatal stress regimen, like neonatal ventral hippocampal lesioning, increases the locomotor response to stimulants and disrupts sensorimotor gating, as well as reducing social drive in the offspring (Sams-Dodd et al, 1997, Lipska and Weinberger, 2000, Le Pen and Moreau, 2002, Rueter et al, 2004. Furthermore, cognitive disturbances (social recognition, novel object recognition) and changes in prefrontal markers of glutamatergic neurotransmission are also present in both of these animal preparations (Le Pen et al, 2000, Lipska et al, 2002, Kinnunen et al, 2003, Koenig, 2005. While some prenatal manipulations in rats, such as immune challenge, viral infection and protein malnutrition also recapitulate sensory gating abnormalities and cognitive disturbances, only unpredictable prenatal stress, hippocampal lesioning and prenatal immune challenge in mice generate social impairments (Borrell et al, 2002, Zuckerman et al, 2003, Palmer et al, 2004.…”

“…Using the overarching hypothesis that mid-gestational stress is a risk factor for schizophrenia, we exposed pregnant female rats to an unpredictable variable stress paradigm, which produces rat offspring with molecular signatures, sensorimotor gating deficits and hyperdopaminergia similar to what has been observed in schizophrenic patients (Kinnunen et al, 2003, Koenig et al, 2005. In the present report, we examined the social phenotype of the adult male rats after exposure to an unpredictable prenatal stress paradigm.…”