Activated microglia impairs neuroglial interaction by opening Cx43 hemichannels in hippocampal astrocytes

• Published in: Glia 2015-05, Vol.63 (5), p.795-811
• Main Authors: Abudara, Verónica, Roux, Lisa, Dallérac, Glenn, Matias, Isabelle, Dulong, Jérôme, Mothet, Jean Pierre, Rouach, Nathalie, Giaume, Christian
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Astrocytes - drug effects; Astrocytes - metabolism; astroglia; Carbenoxolone - pharmacology; CD11b Antigen - metabolism; Connexin 30; Connexin 43 - genetics; Connexin 43 - metabolism; Connexins - deficiency; Connexins - genetics; Connexins - pharmacology; Cytokines - metabolism; gap junctions; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Glutamic Acid - metabolism; Hippocampus - cytology; In Vitro Techniques; Inhibitory Postsynaptic Potentials - drug effects; Inhibitory Postsynaptic Potentials - genetics; Life Sciences; Lipopolysaccharides - pharmacology; Mice, Inbred C57BL; Mice, Transgenic; Microglia - drug effects; Microglia - physiology; Minocycline - pharmacology; Nerve Tissue Proteins - pharmacology; neuroinflammation; Neurons - drug effects; Neurons - physiology; Peptides - pharmacology; Time Factors
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22785

Glia plays an active role in neuronal functions and dysfunctions, some of which depend on the expression of astrocyte connexins, the gap junction channel and hemichannel proteins. Under neuroinflammation triggered by the endotoxin lipopolysacharide (LPS), microglia is primary stimulated and releases proinflammatory agents affecting astrocytes and neurons. Here, we investigate the effects of such microglial activation on astrocyte connexin‐based channel functions and their consequences on synaptic activity in an ex vivo model. We found that LPS induces astroglial hemichannel opening in acute hippocampal slices while no change is observed in gap junctional communication. Based on pharmacological and genetic approaches we found that the LPS‐induced hemichannel opening is mainly due to Cx43 hemichannel activity. This process primarily requires a microglial stimulation resulting in the release of at least two proinflammatory cytokines, IL‐1β and TNF‐α. Consequences of the hemichannel‐mediated increase in membrane permeability are a calcium rise in astrocytes and an enhanced glutamate release associated to a reduction in excitatory synaptic activity of pyramidal neurons in response to Schaffer's collateral stimulation. As a whole our findings point out astroglial hemichannels as key determinants of the impairment of synaptic transmission during neuroinflammation. GLIA 2015;63:795–811 Main Points LPS induces astroglial hemichannel opening in hippocampal slices. This process requires a microglial activation resulting in the production of pro‐inflammatory cytokines that trigger a glutamate release from astrocytes associated to a reduction in excitatory synaptic activity of neurons.