Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca2+ conductances: relevance to brain aging.

Abstract

Glucocorticoids (GCs) activate several biochemical/molecular processes in the hippocampus through two receptor types. In addition, GCs influence cognitive behaviors and hippocampal neural activity and can also increase the rate of aging-dependent cell loss in the hippocampus. However, the ionic mechanisms through which Although it has been recognized for >20 yr that the brain, and in particular the hippocampus, is rich in specific corticosteroid receptors (1, 2), the cellular effects of activating these receptors are still poorly understood (3). Glucocorticoids (GCs) stimulate a number of biochemical and genomic processes in hippocampal neurons (3-5) and have been found by extracellular recording to alter brain neuronal excitability (6-8). Further, stress-related hormones substantially influence memory and other cognitive functions (9, 10). In addition to these normal functions, moreover, chronic exposure to GCs can exert neurotoxic actions on hippocampal pyramidal cells, particularly in conjunction with the brain aging process (11-15). Long-term adrenalectomy protects (12) Recent intracellular electrophysiological studies have provided insights into how brain GCRs may act to modify ionic conductances and neuronal function. Two studies (24,25) found that Cort increases the well-defined (26) Ca2+-dependent, K+-mediated afterhyperpolarization (AHP) that normally follows Na+ action potentials in CA1 hippocampal neurons. This effect of Cort on the AHP likely accounts for inhibitory actions of GCs on hippocampal neurons (24,25) and is mediated by the GCR because it can be mimicked by the highly specific GCR agonist RU 28362 (24). Conversely, further studies have indicated that MCR activation increases hippocampal excitability by suppressing neurotransmittermediated hyperpolarization (for review, see ref. 27). These MCR and GCR effects on hippocampal excitability can be blocked by inhibition of protein synthesis (28).However, it is still not clear how GCs modulate the AHP. Although the effect of GCs on the AHP was suggested to be mediated by an increase in voltage-activated Ca2+ conductance (25), the GC effect could also be mediated by actions on Ca2+ buffering/extrusion or K* channels, among others. Steroids have been shown to influence a number of K+ and Cl-conductances, through actions on membrane receptors (29-31), but to date there has been no evidence that steroids can also influence voltage-sensitive Ca2+ conductance.A clear answer to the question of a putative GC-Ca2+ channel linkage is also of particular relevance to present concepts on mechanisms of brain aging. Elevated intracellular Ca2+ can be neurotoxic, and there is increasing evidence of neuronal Ca2+ dysregulation in brain aging (see refs. 32-37). Because the AHP is increased with aging (25,37), the recent findings that GCs modulate the Ca2+-dependent AHP (24, 25) and, moreover, exert an increased impact in aged neurons (25) suggest that there may be a link between the GC and the Ca2+ dysregulation hypotheses of brain aging. That is, it has b...

Brief RU 38486 Treatment Normalizes the Effects of Chronic Stress on Calcium Currents in Rat Hippocampal CA1 Neurons

“…This contrasts with earlier studies on tissue from younger, naïve rats or mice, where corticosterone was consistently found to enhance Cacurrent amplitude in CA1 cells (Kerr et al, 1992;Karst et al, 1994Karst et al, , 2000. The discrepancies might have been caused by two differences between the present and earlier experimental conditions: first, the present animals were slightly older in age.…”

“…This contrasts with the increased amplitude seen in younger, naïve rats (Kerr et al, 1992;Karst et al, 1994Karst et al, , 2000. Currents in naïve rats of the same age, however, did show enhancement after corticosterone treatment.…”

“…Influx of calcium (Ca) via voltage-gated ion channels for example is very sensitive to MR and GR activation: Predominant MR activation is associated with restricted Ca-influx (Karst et al, 1994;Nair et al, 1998;Joëls et al, 2003). After stress, that is when GRs become activated, Ca-current amplitude increases, with a delay of several hours (Kerr et al, 1992;Karst et al, 1994;Joëls et al, 2003). The increased Ca-influx is due to DNAbinding of GR homodimers (Karst et al, 2000).…”

Corticosteroid Actions in the Hippocampus

“…2). Corticosteroid actions mainly pertain changes in the amplitude of Ca 2+ current components, rather than changes in the voltage dependency or kinetic properties (26,27). The nature of the channels affected is presently unknown, although evidence based on kinetic properties and voltagedependency supports modulation of at least sustained, L-type Ca 2+ -currents (25,26).…”

Corticosterone time-dependently modulates β-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus

“…As argued earlier, the apparent lack of genemediated effects on LTP may be linked to the TBS protocol (Alfarez et al 2002(Alfarez et al , 2003. It should be noted, though, that an apparent lack of gene-mediated corticosteroid effects in the DGpresumably via the low-affinity glucocorticoid receptor (GR)-is not unprecedented, as a similar protocol of corticosterone administration also failed to change calcium currents (van Gemert and Joels 2006) and AMPA-receptor-mediated responses (Karst and Joels 2003) in granule cells, while these parameters are clearly altered by the hormone in the CA1 region (Kerr et al 1992;Karst et al 2000;Karst and Joels 2005). As DG granule cells, like CA1 pyramidal cells, abundantly express GRs, this could signify that DG granule cells (1) express different receptor variants, (2) are exposed to lower intracellular levels of corticosterone, or (3) contain a different set of cellular proteins that determine the transcriptional activity of the GR (Joels 2006).…”