Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact mouse cortex. Upon traumatic brain injury, microglial processes rapidly and autonomously converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. This rapid chemotactic response can be mimicked by local injection of ATP and can be inhibited by the ATP-hydrolyzing enzyme apyrase or by blockers of G protein-coupled purinergic receptors and connexin channels, which are highly expressed in astrocytes. The baseline motility of microglial processes is also reduced significantly in the presence of apyrase and connexin channel inhibitors. Thus, extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglial response towards injury.

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ATP mediates rapid microglial response to local brain injury in vivo

For decades, astrocytes have been considered to be non-excitable support cells of the brain. However, this view has changed radically during the past twenty years. The recent recognition that they are organized in separate territories and possess active properties — notably a competence for the regulated release of 'gliotransmitters', including glutamate — has enabled us to develop an understanding of previously unknown functions for astrocytes. Today, astrocytes are seen as local communication elements of the brain that can generate various regulatory signals and bridge structures (from neuronal to vascular) and networks that are otherwise disconnected from each other. Examples of their specific and essential roles in normal physiological processes have begun to accumulate, and the number of diseases known to involve defective astrocytes is increasing.

Astrocytes, from brain glue to communication elements: the revolution continues.

This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.

/pdf/physiology-and-pathophysiology-of-purinergic-1z94g2hz0f.pdf

Physiology and Pathophysiology of Purinergic Neurotransmission

Saez, Juan C., Viviana M. Berthoud, Maria C. Branes, Agustin D. Martinez, and Eric C. Beyer. Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions. Physiol Rev 83: 1359-1400,...

Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions

Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.

Physiology of astroglia

Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels.

The extracellular concentrations of Ca(2+) and Mg(2+) are well known to play important roles in the function of the central nervous system. We examined the effects of extracellular Ca(2+) and Mg(2+) on ATP release and intercellular signaling in astrocytes. The extent of propagation of intercellular Ca(2+) waves evoked by mechanical stimulation was increased by reduction of extracellular Ca(2+) ([Ca(2+)](o)) or Mg(2+) concentration ([Mg(2+)](o)) and was decreased by elevated [Mg(2+)](o). Reduction of extracellular Ca(2+) concentration ([Ca(2+)](o)) evokes intercellular Ca(2+) signaling in astrocytes; a similar effect was observed in response to change from 5 mM [Mg(2+)](o) to 0 [Mg(2+)](o). Release of low-molecular-weight dyes and ATP was also activated by low [Ca(2+)](o) or [Mg(2+)](o) and inhibited by high [Ca(2+)](o) or [Mg(2+)](o). Astrocytes showed low [Ca(2+)](o)-activated whole cell currents consistent with currents through connexin hemichannels. These currents were inhibited by extracellular Mg(2+). We conclude that extracellular divalent cations modulate intercellular Ca(2+) signaling in astrocytes by modulating the release of ATP, possibly via connexin hemichannels.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/glia.10257

Charles E. Stout

Papers

Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels.

Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium.