Mifepristone Prevents Stress-Induced Apoptosis in Newborn Neurons and Increases AMPA Receptor Expression in the Dentate Gyrus of C57/BL6 Mice

Brian Christie,María Llorens-Martín,José L Trejo

doi:10.1371/journal.pone.0028376

Abstract

Chronic stress produces sustained elevation of corticosteroid levels, which is why it is considered one of the most potent negative regulators of adult hippocampal neurogenesis (AHN). Several mood disorders are accompanied by elevated glucocorticoid levels and have been linked to alterations in AHN, such as major depression (MD). Nevertheless, the mechanism by which acute stress affects the maturation of neural precursors in the dentate gyrus is poorly understood. We analyzed the survival and differentiation of 1 to 8 week-old cells in the dentate gyrus of female C57/BL6 mice following exposure to an acute stressor (the Porsolt or forced swimming test). Furthermore, we evaluated the effects of the glucocorticoid receptor (GR) antagonist mifepristone on the cell death induced by the Porsolt test. Forced swimming induced selective apoptotic cell death in 1 week-old cells, an effect that was abolished by pretreatment with mifepristone. Independent of its antagonism of GR, mifepristone also induced an increase in the percentage of 1 week-old cells that were AMPA+. We propose that the induction of AMPA receptor expression in immature cells may mediate the neuroprotective effects of mifepristone, in line with the proposed antidepressant effects of AMPA receptor potentiators.

Highlights

Adult neurogenesis takes place in the brain of numerous vertebrates [1], including humans [2]
In conjunction with genetic risk factors, the inability to return to the basal state following long- term exposure to high GC levels, known as allostatic load [26], is considered by some authors to be a critical factor in the development of neurodegenerative diseases such as Alzheimers disease (AD) [27] [28] [29], and of mood disorders like major depression (MD) [30] [31]
Chronic stress is widely considered to be a pathogenic factor for major depression (MD) and it provokes a reduction in adult hippocampal neurogenesis (AHN) [52]

Summary

Introduction

Adult neurogenesis takes place in the brain of numerous vertebrates [1], including humans [2]. The physiological response to acute stress and the accompanying increase in GC levels appear to be adaptative in nature, and these events are critical for hippocampal long-term potentiation (LTP) [22] and memory consolidation [23]. In conjunction with genetic risk factors, the inability to return to the basal state following long- term exposure to high GC levels, known as allostatic load [26], is considered by some authors to be a critical factor in the development of neurodegenerative diseases such as Alzheimers disease (AD) [27] [28] [29], and of mood disorders like MD [30] [31]. Chronic exposure to stress induces permanent synaptic and dendritic alterations [34] [35], increases hippocampal glutamate levels [36] [37] and decreases AHN [9]. Understanding the molecular mechanisms that regulate responses to stress, whether chronic or acute (as studied here) is important to identify therapeutic targets that modulate these responses and that avoid the damage caused by prolonged exposure to stress

Methods

Results

Conclusion