https://www.cell.com/trends/neurosciences/pdf/S0166-2236(09)00153-2.pdf

Molecular dissection of reactive astrogliosis and glial scar formation.

Reactive astrocytes: cellular and molecular cues to biological function

NEUROTRANSMITTER released from neurons is known to signal to neighbouring neurons and glia1–3 Here we demonstrate an additional signalling pathway in which glutamate is released from astrocytes and causes an NMDA (N-methyl-d-aspartate) receptor-mediated increase in neuronal calcium. Internal calcium was elevated and glutamate release stimulated by application of the neuro-ligand bradykinin to cultured astrocytes. Elevation of astrocyte internal calcium was also sufficient to induce glutamate release. To determine whether this released glutamate signals to neurons, we studied astrocyte–neuron co-cultures. Bradykinin significantly increased calcium levels in neurons co-cultured with astrocytes, but not in solitary neurons. The glutamate receptor antagonists d-2-amino-5-phosphonopentanoic acid and d-glutamylglycine prevented bradykinin-induced neuronal calcium elevation. When single astrocytes were directly stimulated to increase internal calcium and release glutamate, calcium levels of adjacent neurons were increased; this increase could be blocked by d-glutamylglycine. Thus, astrocytes regulate neuronal calcium levels through the calcium-dependent release of glutamate.

Glutamate-mediated astrocyte-neuron signalling.

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

From a structural perspective, the predominant glial cell of the central nervous system, the astrocyte, is positioned to regulate synaptic transmission and neurovascular coupling: the processes of ...

https://www.physiology.org/doi/pdf/10.1152/physrev.00049.2005

Astrocyte Control of Synaptic Transmission and Neurovascular Coupling

Control of gap-junctional communication in astrocytic networks

It is becoming increasingly clear that astrocytes play very dynamic and interactive roles that are important for the normal functioning of the central nervous system. In culture, astrocytes express many receptors coupled to increases in intracellular calcium ([Ca2+]i). In vivo, it is likely that these receptors are important for the modulation of astrocytic functions such as the uptake of neurotransmitters and ions. Currently, however, very little is known about the expression or stimulation of such astrocytic receptors in vivo. To address this issue, confocal microscopy and calcium-sensitive fluorescent dyes were used to examine the dynamic changes in astrocytic [Ca2+]i within acutely isolated hippocampal slices. Astrocytes were subsequently identified by immunocytochemistry for glial fibrillary acidic protein. In this paper, we present data indicating that hippocampal astrocytes in situ respond to glutamate, kainate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), N-methyl-D-aspartate (NMDA), and depolarization with increases in [Ca2+]i. The increases in [Ca2+]i occurred in both the astrocytic cell bodies and the processes. Temporally the changes in [Ca2+]i were very dynamic, and various patterns ranging from sustained elevations to oscillations of [Ca2+]i were observed. Individual astrocytes responded to neuroligands selective for both ionotropic and metabotropic glutamate receptors with increases in [Ca2+]i. These findings indicate that astrocytes in vivo contain glutamatergic receptors coupled to increases in [Ca2+]i and are able to respond to neuronally released neurotransmitters.

GFAP‐positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca2+]i

Pharmacologically-distinct subsets of astroglia can be identified by their calcium response to neuroligands

We have used the CA++ indicator dye fura-2 AM and computerized imaging systems to investigate adrenergic regulation of intracellular calcium in cultured cerebral type 1 astroglia. We have found that norepinephrine (NE) and other adrenergic agonists stimulate increases in intracellular calcium in over 80% of type 1 astroglia tested. A wide range in effective NE concentrations was seen. With sufficient agonist concentrations the calcium response was biphasic, exhibiting an initial sharp peak followed by a sustained calcium elevation. This secondary component was sensitive to reductions in extracellular calcium concentrations and dependent on the continued presence of agonist. Pharmacological studies indicated that astroglial calcium responses were mediated by alpha 1- and alpha 2-adrenergic receptors. At times these two receptor subtypes appeared to underlie calcium responses by the same cells, whereas other cells only responded to stimulation of one or the other subtypes of alpha-adrenergic receptor. Finally, we have also observed spontaneous and agonist-evoked oscillations in astroglial calcium levels. The major findings of these studies indicate that 1) astroglial cells respond to alpha-adrenergic receptor stimulation with increased intracellular calcium, 2) these responses can be mediated by alpha 1-and/or alpha 2-adrenergic receptors, and 3) subpopulations of cerebral type 1 astroglia exist with respect to alpha-adrenergic receptor expression.

Norepinephrine-evoked calcium transients in cultured cerebral type 1 astroglia.

Primary cultures of neonatal murine brain have been reported to express multiple receptors that regulate adenylate cyclase activity. Since for the most part these results were obtained with mixed cell cultures, it has been difficult to define receptor profiles for specific cell types. With this concern in mind a series of studies has been initiated designed to identify specific receptors present on highly purified, immunocytochemically defined astroglia derived from the cerebral cortices of neonatal rats. In this study the capacity of a variety of peptide hormones to regulate cyclic AMP metabolism in these cells was examined. Fibroblasts derived from the meninges represent a predictable source of contamination in primary CNS culture. Thus, to assign more clearly specific receptors to the astroglial cell population, receptor-mediated regulation of cyclic AMP accumulation was also examined in fibroblasts. Cyclic AMP accumulation in astroglia was stimulated by catecholamines (acting at beta 1-adrenergic receptors), prostaglandin E1, vasoactive intestinal polypeptide, alpha-melanocyte-stimulating hormone, and adrenocorticotropin. Bombesin, luteinizing hormone-releasing hormone, neurotensin, thyrotropin-releasing hormone, somatostatin, secretin, and vasopressin did not significantly increase cyclic AMP levels in these cultures. Catecholamines, acting at alpha 2-adrenergic receptors, and somatostatin inhibited agonist-stimulated cyclic AMP accumulation. In meningeal cell cultures catecholamines (acting at beta 2- and alpha 2-adrenergic receptors) and prostaglandin E1 regulated cyclic AMP levels. However, vasoactive intestinal peptide did not stimulate and somatostatin did not inhibit cyclic AMP accumulation in these cells.

Kenny D Mccarthy

Papers

Control of gap-junctional communication in astrocytic networks

GFAP‐positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca2+]i

Pharmacologically-distinct subsets of astroglia can be identified by their calcium response to neuroligands

Norepinephrine-evoked calcium transients in cultured cerebral type 1 astroglia.

Regulation of cyclic AMP accumulation by peptide hormone receptors in immunocytochemically defined astroglial cells.