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.
Highlights
Major depression disorder (MDD) is a disabling illness that adversely affects subject’s family, behavior, mood, activity and physical health
We found that CPP, a NMDA receptor blocker, strongly abolished the Etd uptake evoked by chronic restraint stress in astrocytes (Figure 6), whereas in microglia and pyramidal neurons caused a small inhibition (Figure 6)
We showed that restraint stress increases the opening of Cx43 and Panx1 hemichannels in astrocytes; whereas Panx1 hemichannels are primarily activated in microglia and neurons
Summary
Major depression disorder (MDD) is a disabling illness that adversely affects subject’s family, behavior, mood, activity and physical health. Acute stress includes adaptive mechanisms necessary for survival, while chronic stress induces over-activation and dysfunction of stress-activated systems, resulting in further brain damage and depressive-like behavior (Sorrells et al, 2009; Popoli et al, 2011). Restraint stress impairs both spatial hippocampal-dependent memory (Luine et al, 1994; Kleen et al, 2006) and hippocampal long-term potentiation (LTP; Pavlides et al, 2002; Alfarez et al, 2003). In the central nervous system (CNS), gliotransmitter release is in part mediated by the opening of hemichannels formed by connexins or pannexins (Wang et al, 2013b). Several independent studies have pointed out that onset and progression of homeostatic imbalances observed during neurodegeneration could be associated to enhanced hemichannel activity in the CNS (Takeuchi et al, 2006; Thompson et al, 2008; Karpuk et al, 2011; Orellana et al, 2011a,b; Gulbransen et al, 2012; Burkovetskaya et al, 2014)
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