Elsevier

Brain Research Reviews

Volume 57, Issue 2, 14 March 2008, Pages 561-570
Brain Research Reviews

Review
Corticosteroid receptors and neuroplasticity

https://doi.org/10.1016/j.brainresrev.2007.06.007Get rights and content

Abstract

The balance in actions mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors in certain regions of the brain, predominantly in the limbic system, appears critical for neuronal activity, stress responsiveness, and behavioral programming and adaptation. Alterations in the MR/GR balance appear to make nervous tissue vulnerable to damage; such damage can have adverse effects on the regulation of the stress response and may increase the risk for psychopathology. Besides the hippocampal formation, other subpopulations of neurons in extra-hippocampal brain areas have been also shown recently to be sensitive to changes in the corticosteroid milieu. From a critical analysis of the available data, the picture that emerges is that the balance (or imbalance) between MR/GR activation influences not only cell birth and death, but also other forms of neuroplasticity. MR occupation appears to promote pro-survival actions, while exclusive GR activation favors neurodegeneration. Interestingly, the sustained co-activation of both receptors, for example in chronic stress conditions, usually results in less drastic effects, restricted to dendritic atrophy and impaired synaptic plasticity. As our knowledge of the plastic changes underpinning the wide spectrum of behavior effects triggered by corticosteroids/stress growths, researchers should be able to better define new targets for therapeutic intervention in stress-related disorders.

Introduction

The limbic system, and in particular the hippocampus and the medial prefrontal cortex (mPFC), serves pivotal roles in cognition (Squire and Zola, 1996) as well as in the regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Accumulating evidence shows that corticosteroid modulation of hippocampal and mPFC activity and plasticity may underlie some aspects of the physiological and behavioral effects of chronic stress. A brief overview of the functional characteristics of corticosteroid receptors will be presented, and their role as key players of the stress-induced functional and structural effects will be revisited, with the intention to provide an integrative perspective on the underpinning mechanisms and their implications in clinical settings.

Section snippets

Corticosteroid receptors

Based on differing biochemical and functional characteristics, two types of corticosteroid receptors were described in the rat brain (Reul and de Kloet, 1985). The so-called Type I, or the high-affinity mineralocorticoid receptor (MR), is most densely localized in hippocampal and septal neurons, but is also present in cortical neurons. The Type II or glucocorticoid receptor (GR) is ubiquitously distributed in neurons and glial cells. Due to their pharmacological properties, MRs are activated at

Electrophysiological actions—within and from the hippocampus

The modulation of neuronal function by corticosteroids is well documented. One example is the induction of long-term potentiation (LTP) in the hippocampus which shows a specific pattern: LTP is observed when corticosteroids are kept within normal basal levels (Diamond et al., 1992), but it is impaired when corticosteroid levels are elevated (e.g. during stress) when, presumably, both GRs and MRs are occupied. Importantly, hypercorticalism is also known to facilitate long-term depression (LTD)

“Endophenotypes” and targets of intervention

Several issues remain unresolved in the field of stress research, one of the most fundamental questions being why, under seemingly similar conditions, some individuals are more vulnerable to stress-induced brain pathology. The wide spectrum of reactions to psychosocial challenges in the normal population varies between two extremes: the ability to mount a robust fight/flight response versus an apparent passive conservation/withdrawal response (Bracha, 2004, McEwen, 2004).

Individual variations

Conclusions and future perspectives

In summary, the evidence reviewed here indicates that MRs and GRs assume opposite roles in regulating synaptic plasticity, especially under stressful conditions. Besides the hippocampus, recent data demonstrate that MR and GR exert differential control over the structure of other brain regions such as the mPFC. MR activation, possibly by recruiting other players (e.g. growth factors), seems to be prerequisite for ‘positive’ neuroplastic events, whereas GR appears to be detrimental for the

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