Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility

Abstract

Why do some individuals succumb to stress and develop debilitating psychiatric disorders, whereas others adapt well in the face of adversity? There is a gap in understanding the neural bases of individual differences in the responses to environmental factors on brain development and functions. Here, using a novel approach for screening an inbred population of laboratory animals, we identified two sub-populations of mice: susceptible mice that show mood-related abnormalities compared to resilient mice, which cope better with stress. This approach combined with molecular and behavioral analyses, led us to recognize, in hippocampus, presynaptic mGlu2 receptors, which inhibit glutamate release, as a stress sensitive marker of individual differences to stress-induced mood disorders. Indeed genetic mGlu2 deletion in mice results in a more severe susceptibility to stress, mimicking the susceptible mouse sub-population. Furthermore, we describe an underlying mechanism by which glucocorticoids, acting via mineralocorticoid receptors (MR), decrease resilience to stress via down regulation of mGlu2 receptors. We also provide a mechanistic link between MR and an epigenetic control of the glutamatergic synapse that underlies susceptibility to stressful experiences. The approach and the epigenetic allostasis concept introduced here serve as a model for identifying individual differences based upon biomarkers and underlying mechanisms and also provide molecular features that may be useful in translation to human behavior and psychopathology.

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

“…In the present study, AFS in naive animals resulted in no significant behavioral changes at the LDT (Fig. S3C) whereas, as reported recently, ARS results in anxiety-like behavior in susceptible mice characterized by an MR-driven down-regulation of mGlu2 receptors in the hippocampus, suggesting that higher MR in susceptible mice may be the result of an early life history of stress (2).…”

“…Recently, mGlu2 receptors have been identified as markers of mood-related behavior and individual responsiveness to stress (2,18); thus, it is noteworthy that we found an opposite trend in mGlu2 expression in CRS mice after exposure to AFS and ARS, with an up-regulation of mGlu2 in CRS mice after exposure to the familiar ARS, but not after exposure to the novel AFS. Previous studies showed that prior daily exposure to the same stressor confers protection from some effects of acute superimposed stressors (29).…”

“…Interestingly, 21-d CRS significantly decreased the transcription of the putative presynaptic mGlu2 receptor (Fig. 1A), an inhibitor of glutamate release that recently has been identified as a marker of mood-related behavior (2,18). There was also a trend to decrease the mRNA for the NR1 of NMDA receptors in the hippocampus (Fig.…”

“…Recently, we discovered that, in susceptible, naive individuals with higher MR levels, ARS induces anxiety-like behavior through a down-regulation of mGlu2 receptors in the hippocampus mediated by the HAT P300 (2). Chromatin immunoprecipitation assays showed that the decrease of P300 expression decreases acetylation of the lysine K27 on the histone H3 bound to the Grm2 promoter, which regulates expression of the mGlu2 receptor (18).…”

“…These differential responses, including determining susceptibility versus resilience to stress, contribute to the pathophysiology of debilitating stress-related disorders (2)(3)(4)(5). The hippocampus is a brain region noted for its plasticity in response to stress and sensitivity to adrenal steroid hormones (6).…”