Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility - PubMed (original) (raw)

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

C Nasca et al. Mol Psychiatry. 2015 Jun.

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 subpopulations of mice: susceptible mice that show mood-related abnormalities compared with 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 (MRs), decrease resilience to stress via downregulation of mGlu2 receptors. We also provide a mechanistic link between MRs 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.

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Figures

Figure 1

Figure 1. mGlu2 knockout mice show a severe susceptibility to stress

a and b, Time course and design of the chronic unpredictable stress (CUS). c, CUS results in a higher immobility time at the FST in mGlu2 knockout mice compared to wild-type mice (F3,72=64.02). Bars represent mean + SEM, * indicate significant comparisons to all other values, ***p < 0.0001. d and e, Body weight and scores at the coat-rating scale over the 4 weeks of CUS in wild-type mice and mGlu2 knock-out mice. Data represent mean + SEM, * indicate significant comparisons to corresponding controls, **p < 0.01, ***p < 0.0001.

Figure 2

Figure 2. Chronic unpredictable stress results in more (HS) and less (LS) susceptible endophenotypes and in individual difference in mGlu2 receptor expression: a molecular signature of susceptibility

a, Time course of the CUS and behavioral outcome analyses b, CUS results in a clear separation in HS and LS-endophenotypes at the coat-state rating scale for the evaluation of the CUS-induced coat deterioration (F14,375=47.19). c, Animal body weight over the four weeks of CUS (F14,375=206.5; F25,350=3.62). d and e, Identification of high and low-susceptible subgroups based on the immobility time at the sucrose intake (d) and at the forced swim test (e) in CUS-mice. Green lines indicate the mean (60.92 in d; 67.08 in e) and the standard deviation (in 15.20; 32.82 in c) of the control group. f, HS-mice show a lower sucrose intake at the sucrose preference test compared to LS wild-type mice subjected to CUS and unstressed mice (F5,66=11.61). g, HS-mice show a higher immobility time at the FST compared to LS wild-type mice subjected to CUS and unstressed mice (F5,74=40.67). Bars represent mean + SEM, * indicate significant comparisons to corresponding controls, ***p < 0.0001. h and i, Western blot analysis and representative blots of HS-mice show lower mGlu2 hippocampal receptor expression compared to CUS-LS mice and unstressed mice (F2,15=264.7). j and k, Western blot analysis and representative blots of mGlu2 receptor expression in the prefrontal cortex (F2,15=185.9) shows a strong impairment in both CUS-HS and CUS-LS mice compared to unstressed mice. Bars represent mean + SEM, * indicate significant comparisons to respective control groups, ***p < 0.0001.

Figure 3

Figure 3. A single episode of stress results in more and less susceptible endophenotypes reminiscent of the CUS-induced HS and LS animal clusters

a, Time course and design of the acute stress and behavioral outcome. b, Identification of high and low-susceptible subgroups based on the time spent in the light chamber at the light dark test in acute restraint stressed-mice. Green lines indicate the mean (153.5) and the standard deviation (42.72) of the control group. c, Acute restraint stress results in behavioral and molecular individual differences that are reminiscent of the CUS HS and LS-endophenotypes. ARS-HS mice spent less time in the light chamber at the LDT compared to ARS-LS mice and unstressed mice (F2,27=10.75). d, ARS-HS mice show lower mGlu2 mRNA transcript levels compared to ARS-LS mice and unstressed mice within the hippocampus (F2,27=8.84) and no difference within the prefrontal cortex (F2,17=0.57). In a and c, bars represent mean + SEM, * indicate significant comparisons to all other values, **p < 0.01. e, Spearman's correlation analysis of hippocampal mGlu2 mRNA levels and time spent in the light chamber at the LDT in HS and LS-mice (r=0.75, p<0.0001).

Figure 4

Figure 4. Glucocorticoids, via hippocampal down-regulation of MR receptors, lead to the loss of suppression of mGlu2 transcripts in resilient mice

a, Acute restraint stress results in lower MR mRNA transcript levels in LS mice compared to HS mice and unstressed mice within the hippocampus (F2,25=44.55) and no difference in GR levels (F2,12=1.32). b, ARS-LS mice compared to ARS-HS mice and unstressed mice show no difference in either MR or GR transcript levels within the PFC (MR: F2,17=2.13; GR:F2,13=0.13). In a and b, bars represent mean + SEM, * indicate significant comparisons to to all other values, **p < 0.01. c, Spearman's correlation analysis of hippocampal MR mRNA levels and time spent in the light chamber at the LDT in HS and LS-mice (r=-0.67, p=0.01). d, Spearman's correlation analysis of hippocampal MR mRNA levels and hippocampal mGlu2 mRNA levels (r=-0.98, p<0.0001). e, Design of the behavioral outcome on naïve mice. f, Naïve mice show behavioral differences in the time spent in the light chamber at the LDT. g, Naïve mice show different MR mRNA transcript levels based on their baseline susceptibility and no difference in mGlu2 mRNA transcript levels. In e and f, bars represent mean + SEM, * indicate significant comparisons, **p < 0.01, ***p < 0.001. h, In the hippocampus, the relationship between MR and mGlu2 mRNA levels can be described by a quadratic curve that models the epigenetic allostasis concept described in the text.

Figure 5

Figure 5. Glucocorticoids, via MR receptors, link stressful experience to an epigenetic control of the glutamatergic synapse

a, Time course and design of the treatments with the selective GR and MR antagonists. b, Spironolactone (20mg/kg, i.p.) alone or in combination with RU486 (also known as mifepristone, 20mg/kg, i.p.), but not RU486 alone, administered 3 hrs prior to the stress exposure, blocks the stress-induced decrease in mGlu2 mRNA transcript levels in the hippocampus of ARS mice c, Chromatin immunoprecipitation assay shows that spironolactone, but not RU486, blocks the stress-induced decrease in H3K27ac bound to the Grm2 promoter gene within the hippocampus. d, Spironolactone abolishes ARS reduction in the HAT p300 mRNA levels. e, Spironolactone, but not RU486, blocks the ARS-induced anxiety-related behavior at the light-dark test. Bars represent mean + SEM, * indicate significant comparisons to control groups, *p < 0.05, **p < 0.01, ***p <0.0001.

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