Stressful events are known to have a long-term impact on future behavioral stress responses. Previous studies suggested that both glucocorticoid hormones and glutamate acting via glucocorticoid receptors (GRs) and N-methyl D-aspartate (NMDA) receptors, respectively, are of critical importance for the consolidation of these longlasting behavioral responses at the dentate gyrus, the gateway of the hippocampal formation. We found that an acute psychologically stressful event resulted in ERK1/2 phosphorylation (pERK1/2), which within 15 min led to the activation of the nuclear kinases MSK1 and Elk-1 in granule neurons of the dentate gyrus. Next, MSK1 and Elk-1 activation evoked serine-10 phosphorylation and lysine-14 acetylation in histone H3, resulting in the induction of the neuroplasticity-associated immediate-early genes c-Fos and Egr-1 in these neurons. The pERK1/2-mediated activation of MSK1 and Elk-1 required a rapid protein-protein interaction between pERK1/2 and activated GRs. This is a unique nongenomic mechanism of glucocorticoid hormone action in dentate gyrus granule neurons on longlasting behavioral responses to stress involving direct cross-talk of GRs with ERK1/2-MSK1-Elk-1 signaling to the nucleus.corticosterone | chromatin | epigenetics | hippocampus | memory A drenal glucocorticoid hormones play an important role in the behavioral consequences of stress (1). Glucocorticoids secreted during a stressful event facilitate learning of adaptive behavioral responses and the consolidation of memories of the event (1, 2). Aberrant glucocorticoid secretion, as a result of chronic stress, is implicated in stress-related disorders such as major depression and anxiety (3-5).It is still unclear how glucocorticoid hormones affect behavior at the molecular level. Glucocorticoid levels attained after stress influence cellular function by activating glucocorticoid receptors (GRs) (6). These receptors bind to their target sites in gene promoters, thereby changing gene expression (7). Activated GRs can also interact through protein-protein interactions with a broad range of intracellular signaling molecules including transcription factors and enzymes (7). Whether GRs directly interact with intracellular signaling pathways to influence stress-related behavior is unknown.A signaling pathway involved in behavioral adaptation and memory formation is the extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) signaling pathway (8). This pathway is activated through N-methyl D-aspartate receptors (NMDA-Rs) and other membrane receptors and is involved in changes in neuronal structure and function (8). Hippocampal NMDA-R-mediated ERK MAPK signaling is involved in behavioral responses observed in Morris water maze learning, contextual fear conditioning, and the forced swim test (9-11). In vitro experiments suggest that ERK MAPK signaling activates nuclear histone modifying enzymes such as MSK1 (mitogen-and stress-activated kinase 1) (12, 13) and Elk-1 (ETS domain protein-1) (14). These enzymes evoke...

A Rs, which can detect extracellular GABA. Such tonic GABA A R-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells in ex vivo hippocampal slices, tonic currents are predominantly generated by GABA-independent GABA A receptor openings. This tonic GABA A R conductance is resistant to the competitive GABA A R antagonist SR95531 (gabazine), which at high concentrations acts as a partial agonist, but can be blocked by an open channel blocker, picrotoxin. When slices are perfused with 200 nM GABA, a concentration that is comparable to CSF concentrations but is twice that measured by us in the hippocampus in vivo using zero-net-flux microdialysis, negligible GABA is detected by dentate granule cells. Spontaneously opening GABA A Rs, therefore, maintain dentate granule cell tonic currents in the face of low extracellular GABA concentrations.

Tonic γ-aminobutyric acid (GABA)A receptor-mediated signalling controls neuronal network excitability in the hippocampus. Although the extracellular concentration of GABA (e[GABA]) is critical in determining tonic conductances, knowledge on how e[GABA] is regulated by different GABA transporters (GATs) in vivo is limited. Therefore, we studied the role of GATs in the regulation of hippocampal e[GABA] using in vivo microdialysis in freely moving rats. Here we show that GAT-1, which is predominantly presynaptically located, is the major GABA transporter under baseline, quiescent conditions. Furthermore, a significant contribution of GAT-3 in regulating e[GABA] was revealed by administration of the GAT-3 inhibitor SNAP-5114 during simultaneous blockade of GAT-1 by NNC-711. Thus, the GABA transporting activity of GAT-3 (the expression of which is confined to astrocytes) is apparent under conditions in which GAT-1 is blocked. However, sustained neuronal activation by K+-induced depolarization caused a profound spillover of GABA into the extrasynaptic space and this increase in e[GABA] was significantly potentiated by sole blockade of GAT-3 (i.e. even when uptake of GAT-1 is intact). Furthermore, experiments using tetrodotoxin to block action potentials revealed that GAT-3 regulates extrasynaptic GABA levels from action potential-independent sources when GAT-1 is blocked. Importantly, changes in e[GABA] resulting from both GAT-1 and GAT-3 inhibition directly precipitate changes in tonic conductances in dentate granule cells as measured by whole-cell patch-clamp recording. Thus, astrocytic GAT-3 contributes to the regulation of e[GABA] in the hippocampus in vivo and may play an important role in controlling the excitability of hippocampal cells when network activity is increased.

A strict control of glucocorticoid hormone responses to stress is essential for health. In blood, glucocorticoid hormones are for the largest part bound to corticosteroid-binding globulin (CBG), and just a minor fraction of hormone is free. Only free glucocorticoid hormone is able to exert biological effects, but little is known about its regulation during stress. We found, using a dual-probe in vivo microdialysis method, that in rats, the forced-swim stress-induced rise in free corticosterone (its major glucocorticoid hormone) is strikingly similar in the blood and in target compartments such as the subcutaneous tissue and the brain. However, in all compartments, the free corticosterone response was delayed by 20-30 min as compared with the total corticosterone response in the blood. We discovered that CBG is the key player in this delay. Swim stress evoked a fast (within 5 min) and profound rise in CBG protein and binding capacity in the blood through a release of the protein from the liver. Thus, the increase in circulating CBG levels after stress restrains the rise in free corticosterone concentrations for approximately 20 min in the face of mounting total hormone levels in the circulation. The stress-induced increase in CBG seems to be specific for moderate and strong stressors. Both restraint stress and forced swimming caused an increase in circulating CBG, whereas its levels were not affected by mild novelty stress. Our data uncover a new, highly dynamic role for CBG in the regulation of glucocorticoid hormone physiology after acute stress.

The neurophysiology of non-rapid eye movement sleep is characterized by the occurrence of neural network oscillations with distinct origins and frequencies, which act in concert to support sleep-dependent information processing. Thalamocortical circuits generate slow (0.25-4 Hz) oscillations reflecting synchronized temporal windows of cortical activity, whereas concurrent waxing and waning spindle oscillations (8-15 Hz) act to facilitate cortical plasticity. Meanwhile, fast (140-200 Hz) and brief (< 200 ms) hippocampal ripple oscillations are associated with the reactivation of neural assemblies recruited during prior wakefulness. The extent of the forebrain areas engaged by these oscillations, and the variety of cellular and synaptic mechanisms involved, make them sensitive assays of distributed network function. Each of these three oscillations makes crucial contributions to the offline memory consolidation processes supported by non-rapid eye movement sleep. Slow, spindle and ripple oscillations are therefore potential surrogates of cognitive function and may be used as diagnostic measures in a range of brain diseases. We review the evidence for disrupted slow, spindle and ripple oscillations in schizophrenia, linking pathophysiological mechanisms to the functional impact of these neurophysiological changes and drawing links with the cognitive symptoms that accompany this condition. Finally, we discuss potential therapies that may normalize the coordinated activity of these three oscillations in order to restore healthy cognitive function.