Individual Stress Vulnerability Is Predicted by Short-Term Memory and AMPA Receptor Subunit Ratio in the Hippocampus

Abstract

Increased vulnerability to aversive experiences is one of the main risk factors for stress-related psychiatric disorders as major depression. However, the molecular bases of vulnerability, on the one hand, and stress resilience, on the other hand, are still not understood. Increasing clinical and preclinical evidence suggests a central involvement of the glutamatergic system in the pathogenesis of major depression. Using a mouse paradigm, modeling increased stress vulnerability and depression-like symptoms in a genetically diverse outbred strain, and we tested the hypothesis that differences in AMPA receptor function may be linked to individual variations in stress vulnerability. Vulnerable and resilient animals differed significantly in their dorsal hippocampal AMPA receptor expression and AMPA receptor binding. Treatment with an AMPA receptor potentiator during the stress exposure prevented the lasting effects of chronic social stress exposure on physiological, neuroendocrine, and behavioral parameters. In addition, spatial short-term memory, an AMPA receptor-dependent behavior, was found to be predictive of individual stress vulnerability and response to AMPA potentiator treatment. Finally, we provide evidence that genetic variations in the AMPA receptor subunit GluR1 are linked to the vulnerable phenotype. Therefore, we propose genetic variations in the AMPA receptor system to shape individual stress vulnerability. Those individual differences can be predicted by the assessment of shortterm memory, thereby opening up the possibility for a specific treatment by enhancing AMPA receptor function.

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

“…In a previous study applying a slightly different chronic defeat model, Homer1 expression was also reported to be upregulated in the nucleus accumbens (Berton et al, 2006). Furthermore, microarray data from another study in our lab indicated hippocampal Homer1 to be differentially regulated between stress-resilient and -vulnerable animals (Schmidt et al, 2010), further strengthening the evidence of Homer1 being involved in stress-induced psychopathology. At least on the mRNA level, the effects of chronic stress were specific to the Homer1b/c splice variant, whereas the expression of the immediate early gene Homer1a was not affected.…”

“…RNA was isolated from whole hippocampi using the TRIZOL reagent (Invitrogen) as previously described (Schmidt et al, 2010). The quality of the RNA was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA).…”

Glucocorticoids act on glutamatergic pathways to affect memory processes

“…Another important peculiarity of this study is that the facilitating cognitive actions of glucocorticoids were observed in memory tests delivered several hours after treatment [58]. In fact, substantial evidence indicates that when stress or glucocorticoid elevations occur either shortly before or during working memory performance, an impairment is observed [12,59,60].…”

“…Working memory -as tested in a PFC-dependent Tmaze delayed alternation task -was improved, in a GRdependent manner, when rats were tested at 4 h or 24 h, but not at 48 h after forced-swim stress. Stress and corticosterone increased postsynaptic glutamatergic transmission via GRs -most likely through the observed postsynaptic delivery of AMPARs and NMDARs -in the PFC ( [57]; but note that a negative correlation was recently found between hippocampal GluA2 expression and short-term memory [58]). However, in contrast to the examples discussed previously in this section, the stress/glucocorticoids whose cognitive effects were explored in this latter working-memory study [58] are not those elicited by training, but were instead Box 3.…”

Seeing the Future: Epigenetic Biomarkers of Postpartum Depression

“…Whether our identified biomarkers represent a mere proxy of estrogen sensitivity or are involved in PPD pathophysiology will require further study. TTC9B may be linked to regulation of AMPA receptor levels, which in turn have been shown to be associated with resilience or vulnerability to stress (Schmidt et al, 2010). If the molecular changes exhibited by the biomarkers indicate a biological vulnerability, these may interact with stress occurring in the postnatal period and ultimately lead to depression.…”