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Corticosteroids: way upstream - PubMed

  • ️Fri Jan 01 2010

Review

Corticosteroids: way upstream

Therese Riedemann et al. Mol Brain. 2010.

Abstract

Studies into the mechanisms of corticosteroid action continue to be a rich bed of research, spanning the fields of neuroscience and endocrinology through to immunology and metabolism. However, the vast literature generated, in particular with respect to corticosteroid actions in the brain, tends to be contentious, with some aspects suffering from loose definitions, poorly-defined models, and appropriate dissection kits. Here, rather than presenting a comprehensive review of the subject, we aim to present a critique of key concepts that have emerged over the years so as to stimulate new thoughts in the field by identifying apparent shortcomings. This article will draw on experience and knowledge derived from studies of the neural actions of other steroid hormones, in particular estrogens, not only because there are many parallels but also because 'learning from differences' can be a fruitful approach. The core purpose of this review is to consider the mechanisms through which corticosteroids might act rapidly to alter neural signaling.

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Figures

Figure 1
Figure 1

Schematic representation of the hypothalamo-pituitary-adrenal (HPA) axis and its neuronal inputs. Corticotropin-releasing hormone (CRH)- and arginine vasopressin (AVP)-expressing parvocellular neurons in the paraventricular nucleus (PVN) project to pituitary (via the median eminence) where they stimulate adrenocorticotrophic hormone (ACTH) synthesis and secretion, subsequently triggering corticosteroid synthesis and release from the adrenal cortex. Besides acting in the brain to regulate various behaviours, corticosteroids fine-tune the subsequent pattern (amplitude and duration) of corticosteroid secretion; they activate their cognate receptors in the pituitary, hypothalamus and hippocampus and bed nucleus of the stria terminalis (BNST, a relay between the hippocampus/amygdala and the PVN) to restrain, and in the amygdala to enhance, adrenocortical secretion. Monoaminergic transmitters, namely, norepinephrine, serotonin and dopamine released from midbrain nuclei (the locus coeruleus [LC], raphé and ventral tegmental area [VTA] and substantia nigra [SN], respectively) exert modulatory effects on all brain regions involved in the control of the HPA axis. 'Plus' signs (green) indicate positive drive on the HPA axis; 'minus' signs (red) represent sites of corticosteroid negative feedback; 'clock' signs denote neuronal populations known to respond rapidly to corticosteroids. Corticosteroids are secreted rhythmically, displaying ultradian and circadian patterns. The circadian peak coincides with the onset of the daily activity cycle (dark phase in rodents, light phase in humans). While the physiological and behavioural significance of the ultradian rhythms of corticosteroid secretion is still unclear, it is plausible that they serve to dynamically fine-tune the regulation of the HPA axis and thus, to facilitate adaptive processes. LD, light-dark cycle.

Figure 2
Figure 2

Schematic representation of induction and recording of long-term potentation and long term depression in the hippocampus. Long-term potentiation (LTP) and long-term depression (LTD) can be induced by applying an electrical stimulus by placing an electrode placed in the Schaffer collateral-commissural (SCC) pathway and recording from the CA1 subfield. Upper panel shows a coronal section through the dorsal hippocampus, with schematic representation of intra-hippocampal connectivity. The CA1 pyramidal cell layer receives input from the entorhinal cortex through the dentate gyrus [DG] and the CA3 pyramidal layers and the SCC; the subiculum carries hippocampal efferents. Lower left-hand panel illustrates measurements of LTP as excitatory postsynaptic potentials (EPSP, peak amplitude or slope of the latter). Initially, low-frequency stimulation (LFS, usually less than 0.1 Hz) is applied to the Schaffer collaterals to establish a stable baseline (usually for 20-30 min), after which LTP is induced by high-frequency stimulation (HFS; usually 100 Hz), followed by LFS. Successful induction of LTP can be assumed when the post-HFS EPSP peak amplitude (or slope) exceeds that seen before HFS and is maintained for at least 60 min. ① depicts a single evoked EPSP; ② represents a potentiated EPSP after HFS. Lower right-hand panel shows that EPSP recordings also serve to detect LTD. After initial baseline recording, low-frequency stimulation (LFS, usually 1 or 5 Hz) is applied to the SCC; successfully induced LTD can be assumed when the post-LFS EPSP peak amplitude (or slope) is smaller than that observed before LFS. ① shows a single baseline EPSP; ② depicts a example of a depressed EPSP after LFS.

Figure 3
Figure 3

Schematic representation of corticosteroid-triggered multiple tentative rapidly influencing neuronal function. Corticosteroids are represented by red triangles. Nuclear GR (nGR) interact with caveolins [cf. [81]]; the interaction probably depends on posttranslational modifications of nGR to yield so-called membrane corticosteroid receptors (mCR). Alternatively, CS-initiated intracellular signaling cascades may result from corticosteroid binding to proteins embedded in the plasma membrane, e.g. G-protein-coupled receptors (GPCR) [75] which, upon activation, activate protein kinase A (PKA) and protein kinase C (PKC) in turn. Other evidence points to membrane-bound corticosteroid binding proteins that interact with members of the src family of kinases (SFK) to activate the mitogen-activated protein kinase (MAPK) pathway and/or modulate the activity of other membrane-associated proteins, e.g. NMDA receptors and other ion channels with potential steroid binding sites [76,85,86,222]. Under basal conditions, nGR are tethered in the cytoplasm in the form of a protein complex that includes the chaperone heat shock protein 90 (hsp90) which itself may directly interact with Src kinases and the MAPK kinase, MEK [cf. [83]]. Additionally, direct interactions between the nGR and Ras which may be functionally relevant have been described [84]. Finally, MAPK-mediated phsophorylation of nGR may influence the transcriptional activity of nGR [32]. Thus, corticosteroid actions at the plasma membrane can converge and prime or potentiate hormonal actions on gene transcription.

Figure 4
Figure 4

Working model of sequential corticosteroid influences on synaptic physiology. Corticosterone-mediated changes in synaptic transmission occur at different levels and in different sequential steps. ① depicts synaptic transmission under basal conditions. Neuronal excitation results in glutamate secretion from synaptic vesicles at presynaptic sites into the synaptic cleft. Glutamate binds to postsynaptic glutamate-gated ion channels (in particular, AMPA receptors), which open to permit ion fluxes (Na+ influx, K+ efflux) across the AMPA receptor, resulting in a depolarization of the postsynaptic cell. Due to a voltage-dependent Mg2+ block in its membrane domain, the NMDA receptor remains inactive under basal conditions, and is activated when a certain transmission threshold is reached. ② Exposure to corticosteroids (e.g. during stress) may lead to activation of ERK1/2 in the presynaptic terminal (possibly through membrane corticosteroid receptors [51]); increased glutamatergic stimulation of postsynaptic AMPA receptors results in an increase in the frequency of AMPA receptor-mediated miniature postsynaptic currents (mEPSCs). ③ Enhanced activation of AMPA receptors in the previous step further depolarizes the postsynaptic membrane and activates NMDA receptors. Activated NMDA receptors (Na+ and Ca2+ influx, K+ efflux) lead to further depolarization of the postsynaptic cell, resulting in the opening of voltage-dependent Ca2+ channels (VDCC) and high postsynaptic concentrations of Ca2+. Corticosteroids may stimulate glutamate secretion so strongly, causing glutamate "spill-over" which activates not only synaptic, but also extrasynaptic, glutamate receptors [141]; the latter are mainly NMDA receptors of the NR2B subtype. The increased intracellular levels of Ca2+ trigger a cascade of Ca2+-dependent signaling pathways in the postsynaptic cell, which may, in turn, induce the phosphorylation and de-phosphorylation of postsynaptic glutamatergic receptors and of nuclear corticosteroid receptors (nMR and nGR). Activation of extrasynaptic NMDA receptors is thought to trigger NR2B-dependent kinases, which might initiate trafficking of extrasynaptic NR2B receptors into the postsynaptic surface. Furthermore, Ca2+-dependent signaling pathways in the postsynaptic cell participate in the regulation of AMPA receptor trafficking to and from the synaptic surface, as indicated in ④. Phosphorylation of nuclear corticosteroid receptors, influences their translocation to the nucleus and therefore, their transcriptional activity [32], as indicated in ⑤.

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