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...

There is increasing evidence that experimental interventions that alter adrenal corticosteroid plasma concentrations can modulate aging changes in the rodent hippocampus. However, there still is very little evidence that elevation of endogenous corticosteroid levels within physiological ranges, such as occurs during chronic stress, can accelerate hippocampal aging-like changes. In addition, almost all prior intervention studies of corticosteroid effects on brain biomarkers of aging have utilized morphologic measures of aging, and it is not yet clear whether electrophysiologic biomarkers of hippocampal aging can also be accelerated by conditions that elevate corticosteroids. In the present studies, specific pathogen-free rats of three ages (4, 12, and 18 months at the start) were trained for 6 months (4 hr/d, 5 d/week) in a two-way shuttle escape task, using low intensity foot shock. This task induces "anxiety" stress, because animals receive little actual shock, but chronic training in the task has been shown to elevate plasma corticosteroids and to downregulate hippocampal corticosteroid receptors. At the end of 6 months, animals were allowed to recover for 3 weeks and were then assessed in acute, anesthetized preparations on a battery of hippocampal neurophysiological markers known to separate young from aged animals (frequency potentiation, synaptic excitability thresholds, EPSP amplitude). The brains were then fixed and sectioned for quantification of neuronal density in field CA1 (a highly consistent anatomic marker of hippocampal aging). The pattern of stress effects differed considerably across age groups. The two younger stress groups exhibited increased evidence of aging-like neurophysiologic change, but exhibited no indications of accelerated neuronal loss.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper reviews evidence that brain aging and Alzheimer's disease (AD) are somehow closely related and that the hippocampus (CA1) is highly vulnerable to cell loss under both conditions. In addition, two current lines of evidence on the mechanisms of hippocampal cell loss with aging are considered, including studies of neuronal calcium dysregulation and studies of cumulative glucocorticoid (GC) neurotoxicity. Moreover, recent electrophysiological studies have shown that excess glucocorticoid activation of hippocampal neurons increases the influx of calcium through voltage-activated calcium channels. Second messenger systems may mediate the steroid modulation of calcium channels. Therefore, it is hypothesized that excess glucocorticoid activation and neuronal calcium dysregulation may be two phases of a single process that increases the susceptibility of neurons to neurodegeneration during aging and Alzheimer's disease.

There is growing interest in the phenomenon of long-term depression (LTD) of synaptic efficacy that, together with long-term potentiation (LTP), is a putative information storage mechanism in mammalian brain. In neural network models, multiple learning rules have been used for LTD induction. Similarly, in neurophysiological studies of hippocampal synaptic plasticity, a variety of activity patterns have been effective at inducing LTD, although experimental paradigms are still being optimized. In this review the authors summarize the major experimental paradigms and compare what is known about the mechanisms of LTD induction. Although all paradigms appear to initiate a cascade of events leading to an elevated level of Ca2+ postsynaptically, the extent to which these paradigms involve common expression mechanisms has not yet been tested. The authors discuss several critical experiments that would address this latter issue. Numerous questions about the properties and mechanisms of LTD(s) in the hippocampus remain to be answered, but it is clear that LTD has finally arrived, and will soon be attracting attention equal to its flip side, LTP.