Physiological Elevations of Glucocorticoids Potentiate Glutamate Accumulation in the Hippocampus

Abstract

Glucocorticoids (GCs) are secreted during stress and can damage the hippocampus over the course of aging and impair the capacity of hippocampal neurons to survive excitotoxic insults. Using microdialysis, we have previously observed that GCs augment the extracellular accumulation of glutamate and aspartate in the hippocampus following kainic acid‐induced seizures. In that study, adrenalectomized rats maintained on minimal GC concentrations were compared with those exposed to GCs elevated to near‐pharmacological levels. We wished to gain insight into the physiological relevance of these observations. Thus, we have examined the effects of GCs over the normal physiological range on glutamate and aspartate profiles; this was done by implanting adrenalectomized rats with GC‐secreting pellets, which produce stable and controllable circulating GC concentrations. We observe that incremental increases in GC concentrations cause incremental increases in glutamate accumulation before the kainic acid insult, as well as in the magnitude of the glutamate response to kainic acid. Elevating GC concentrations from the circadian trough to peak doubled cumulative glutamate accumulation, whereas a rise into the stress range caused a fourfold increase in accumulation. Similar, although smaller, effects also occurred with aspartate accumulation (as well as with taurine but not glutamine accumulation). These data show that the highly elevated GC concentrations that accompany neurological insults such as seizure or hypoxia‐ischemia will greatly exacerbate the glutamate accumulation at that time. Furthermore, stress levels of GCs augmented glutamate accumulation even in the absence of an excitotoxic insult, perhaps explaining how sustained stress itself damages the hippocampus. Finally, even the moderately ėlevated basal GC concentrations that typically occur in aged rats augmented glutamate accumulation, perhaps explaining how GCs damage the hippocampus over the course of normal aging.

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

“…Elevation of these proinflammatory factors is accompanied with dendritic atrophy and neuronal death within the hippocampus, 161,162 which are also found in brains of subjects with MD. These detrimental effects of glucocorticoids in the CNS are mediated by a rise in extracellular glutamate 163,164 and subsequent overstimulation of the NMDA receptor. Such an overstimulation of the NMDA receptor results in excitotoxic neuronal damage.…”

Chronic stress enhances methamphetamine‐induced extracellular glutamate and excitotoxicity in the rat striatum

“…Furthermore, the increases in extracellular GLU in various brain areas after exposure to acute or chronic stressors (Broom and Yamamoto, 2005;Lowy et al, 1995;Moghaddam, 1993) are attenuated by adrenalectomy (Lowy et al, 1993;Moghaddam et al, 1994). Moreover, elevations in glucocorticoids or psychological stress exacerbate the increase in extracellular GLU, neuron loss, and spectrin proteolysis in the hippocampus produced by kainic acid (Stein-Behrens et al, 1992, 1994b.…”

Neural stem cells and the regulation of neurogenesis in the adult hippocampus

“…Transient global ischemia increases proliferation in the SGL by 12-fold between 6 and 11 days after surgery. There is a threefold increase in the number of new neurons 28 days after the last BrdU injection [18]. Interestingly, it has been shown that some of the effects of ischemia on the brain may mediated by NMDA and AMPA receptors [40,41].…”

“…As reviewed above, proliferation and neuronal recruitment in the adult dentate gyrus can be altered by adrenal steroids [15,28], the blockade of NMDA receptors [33], estrogen [19], seizures [17,20], ischemia [18], serotonin [23], opiate [24] and lithium administration [25]. Although all these treatments probably have different modes of action, they may all result in changes in granule neuron activity and/or their extracellular microenvironment within the GCL, which in turn may alter the proliferation of neuronal precursors in the SGL.…”

“…Recent work in the hippocampus indicates that new neurons are derived from dividing dentate gyrus radial astrocytes [14]. Several other studies have described experimental interventions that affect proliferation, recruitment and incorporation of new neurons in the adult dentate gyrus [15][16][17][18][19][20][21][22][23][24][25]. Those studies, however, were done before the primary progenitors in the adult hippocampus were identified and could not link effects on proliferation, generation and survival of new neurons to possible alterations in the behavior of the stem cells.…”