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

For decades, studied have been focusing on the neuronal abnormalities that accompany neurodegenerative disorders. However, it is becoming increasingly evident that glial cells are also important players in numerous neurological diseases. Because reactive astrocytes are associated with a variety of central nervous system (CNS) disorders, interest in the glial contribution to neuronal injury is exponentially increasing. Astrocytes, the main type of glia in the CNS, form extensive networks that physically and functionally connect the neuronal synapses with cerebral blood vessels. Normal brain functioning strictly depends on a highly detailed, cellular cross-talk between these different partners to which Ca2+ ions largely contribute. An alteration of intracellular Ca2+ levels in response to many neurodegenerative insults plays a crucial role in glial responses in the injured brain. Most importantly, Ca2+ increases in single astrocytes can be propagated toward neighboring cells, thereby recruiting a larger group of cells and giving rise to so-called intercellular Ca2+ waves (ICWs). The propagation of intercellular Ca2+ largely can depend on two, parallel, connexin (Cx) channel based mechanisms: the diffusion of inositol 1,4,5 trisphosphate through gap junction channels which directly connect the cytoplasm of neighboring cells or 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 between astrocytes in brain physiology and pathology, focusing on the processes of neurodegeneration, reactive gliosis and blood-brain barrier permeability. Research on Cx-mediated astroglial Ca2+ communication may ultimately shed light on the development of targeted therapies for neurodegenerative disorders in which astrocytes participate.