Restraint stress increases hemichannel activity in hippocampal glial cells and neurons

Abstract

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.

Loss of Hippocampal Oligodendrocytes Contributes to the Deficit of Contextual Fear Learning in Adult Rats Experiencing Early Bisphenol A Exposure

“…During early development, unlimited exposure to social and environmental risk factors, such as early life stress, has been known to have lasting negative impacts on the brain and precipitates the development of mental illness later in life [43][44][45]. Both neurons and glia cells in the brain were reported to be the sites of the actions of these challenges [46]. For example, repeated restraint stress was shown to have lasting but contrasting influences on the production of hippocampal neurons and OLs [47].…”

Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

“…Microglial Panx1 and Cx HCs also release purinergic‐signaling molecules under inflammatory conditions. In a report by Orellana et al (), restraint stress increased hippocampal microglial, astrocyte, and neuronal ethidium bromide uptake, which was abrogated by application of the Panx1 HC blocking peptide 10 panx1 but not Cx43 HC blockers (Orellana et al, ). These changes in dye uptake were abolished by application of ionotropic purinergic receptor P2X 7 and NMDAR antagonists, but not metabotropic purinergic P2Y 1 receptor blockade, and were accompanied by increased extracellular glutamate and ATP (Orellana et al, ).…”

“…In a report by Orellana et al (), restraint stress increased hippocampal microglial, astrocyte, and neuronal ethidium bromide uptake, which was abrogated by application of the Panx1 HC blocking peptide 10 panx1 but not Cx43 HC blockers (Orellana et al, ). These changes in dye uptake were abolished by application of ionotropic purinergic receptor P2X 7 and NMDAR antagonists, but not metabotropic purinergic P2Y 1 receptor blockade, and were accompanied by increased extracellular glutamate and ATP (Orellana et al, ). This suggests that ionotropic purinergic signaling downstream of Panx1‐mediated gliotransmitter release may be a vehicle of microglial HC dysfunction during inflammatory conditions, such as those generated by chronic stress (Walker, Nilsson, & Jones, ).…”

New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

“…Relevant to this point, increased levels of [Ca 2+ ] i , iNOS, and COX 2 activation, as well as production of NO, underpin the Panx1 channel-dependent release of ATP in LPS-stimulated microglia (Orellana et al, 2013), whereas NO-mediated Cx43 s-nitrosylation is pivotal in the activation of astroglial hemichannels triggered by oxidative stress (Retamal et al, 2006). Importantly, the stimulation of these pathways has been linked to glial hemichannel/pannexon activation under different pathological conditions, including amyloid β treatment (Gajardo-Gómez et al, 2017), prenatal inflammation (Avendaño et al, 2015), restraint stress (Orellana et al, 2015), spinal cord injury (Garré et al, 2016), high cholesterol diet (Orellana et al, 2014b), AD (Yi et al, 2016), and Niemann-Pick type C disease (Sáez et al, 2013). …”