Stress affects brain areas involved in learning and emotional responses, which may contribute in the development of cognitive deficits associated with major depression. These effects have been linked to glial cell activation, glutamate release and changes in neuronal plasticity and survival including atrophy of hippocampal apical dendrites, loss of synapses and neuronal death. Under neuro-inflammatory conditions, we recently unveiled a sequential activation of glial cells that release ATP and glutamate via hemichannels inducing neuronal death due to activation of neuronal NMDA/P2X7 receptors and pannexin1 hemichannels. In the present work, we studied if stress-induced glia activation is associated to changes in hemichannel activity. To this end, we compared hemichannel activity of brain cells after acute or chronic restraint stress in mice. Dye uptake experiments in hippocampal slices revealed that acute stress induces opening of both Cx43 and Panx1 hemichannels in astrocytes, which were further increased by chronic stress; whereas enhanced Panx1 hemichannel activity was detected in microglia and neurons after acute/chronic and chronic stress, respectively. Moreover, inhibition of NMDA/P2X7 receptors reduced the chronic stress-induced hemichannel opening, whereas blockade of Cx43 and Panx1 hemichannels fully reduced ATP and glutamate release in hippocampal slices from stressed mice. Thus, we propose that gliotransmitter release through hemichannels may participate in the pathogenesis of stress-associated psychiatric disorders and possibly depression.

The mechanisms involved in Alzheimer's disease are not completely understood and how astrocytes and their gliotransmission contribute to this neurodegenerative disease remains to be fully elucidated. Previous studies have shown that amyloid‐β peptide (Aβ) induces neuronal death by a mechanism that involves the excitotoxic release of ATP and glutamate associated to astroglial hemichannel opening. We have demonstrated that synthetic and endogenous cannabinoids (CBs) reduce the opening of astrocyte Cx43 hemichannels evoked by activated microglia or inflammatory mediators. Nevertheless, whether CBs could prevent the astroglial hemichannel‐dependent death of neurons evoked by Aβ is unknown. Astrocytes as well as acute hippocampal slices were treated with the active fragment of Aβ alone or in combination with the following CBs: WIN, 2‐AG, or methanandamide (Meth). Hemichannel activity was monitored by single channel recordings and by time‐lapse ethidium uptake while neuronal death was assessed by Fluoro‐Jade C staining. We report that CBs fully prevented the hemichannel activity and inflammatory profile evoked by Aβ in astrocytes. Moreover, CBs fully abolished the Aβ‐induced release of excitotoxic glutamate and ATP associated to astrocyte Cx43 hemichannel activity, as well as neuronal damage in hippocampal slices exposed to Aβ. Consequently, this work opens novel avenues for alternative treatments that target astrocytes to maintain neuronal function and survival during AD. GLIA 2016 GLIA 2017;65:122–137

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Exposure to high levels of glucocorticoids (GCs) during early life induces long-lasting neuroinflammation. GCs induce rapid degranulation of mast cells, which release proinflammatory molecules promoting activation of microglia and astrocytes. The possible involvement of oligodendrocytes, however, remains poorly understood. It was studied whether high GC levels during gestation activates the inflammasome in hippocampal oligodendrocytes of mouse offspring. Oligodendrocytes of control pups showed expression of inflammasome components (NLRP3, ACS, and caspase-1) and their levels were increased by prenatal administration of dexamethasone (DEX), a synthetic GC. These cells also showed high levels of IL-1β and TNF-α, revealing activation of the inflammasome. Moreover, they showed increased levels of the P2X receptor and pannexin1, which are associated to inflammasome activation. However, levels of connexins either were not affected (Cx29) or reduced (Cx32 and Cx47). Nonetheless, the functional states of pannexin1 and connexin hemichannels were elevated and directly associated to functional P2X receptors. As observed in DEX-treated brain slices, hemichannel activity first increased in hippocampal mast cells and later in microglia and macroglia. DEX-induced oligodendrocyte hemichannel activity was mimicked by urocortin-II, which is a corticotropin-releasing hormone receptor (CRHR) agonist. Response to DEX and urocortin-II was inhibited by antalarmin (a CRHR blocker) or by mast cells or microglia inhibitors. The increase in hemichannel activity persisted for several weeks after birth and cross-fostering with a control mother did not reverse this condition. It is proposed that activation of the oligodendrocyte inflammasome might be relevant in demyelinating diseases associated with early life exposure to high GC levels. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 625-642, 2017.