The dual face of connexin-based astroglial Ca2 + communication: A key player in brain physiology and a prime target in pathology

• Glial cells are important players in brain physiology and pathology.
• Connexin channels mediate intercellular Ca2 + signaling in the astrocytic network.
• Intercellular Ca2 + signaling plays a crucial role at the neurogliovascular unit.
• Glial intercellular Ca2 + signaling is observed in different brain disease models.
• Neurodegeneration and -inflammation are tightly linked to intercellular signaling.

For decades, studies have been focusing on the neuronal abnormalities that accompany neurodegenerative disorders. Yet, glial cells are emerging as important players in numerous neurological diseases. Astrocytes, the main type of glia in the central nervous system , form extensive networks that physically and functionally connect neuronal synapses with cerebral blood vessels. Normal brain functioning strictly depends on highly specialized cellular cross-talk between these different partners to which Ca2 +, as a signaling ion, largely contributes. Altered intracellular Ca2 + levels are associated with neurodegenerative disorders and play a crucial role in the glial responses to injury. Intracellular Ca2 + increases in single astrocytes can be propagated toward neighboring cells as intercellular Ca2 + waves, thereby recruiting a larger group of cells. Intercellular Ca2+ wave propagation depends on two, parallel, connexin (Cx) channel-based mechanisms: i) the diffusion of inositol 1,4,5-trisphosphate through gap junction channels that directly connect the cytoplasm of neighboring cells, and ii) the release of paracrine messengers such as glutamate and ATP through hemichannels (‘half of a gap junction channel’). This review gives an overview of the current knowledge on Cx-mediated Ca2 + communication among astrocytes as well as between astrocytes and other brain cell types in physiology and pathology, with a focus on the processes of neurodegeneration and reactive gliosis. Research on Cx-mediated astroglial Ca2 + communication may ultimately shed light on the development of targeted therapies for neurodegenerative disorders in which astrocytes participate. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.