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.

Brain-derived neurotrophic factor (BDNF)--a member of a small family of secreted proteins that includes nerve growth factor, neurotrophin 3 and neurotrophin 4--has emerged as a key regulator of neural circuit development and function. The expression, secretion and actions of BDNF are directly controlled by neural activity, and secreted BDNF is capable of mediating many activity-dependent processes in the mammalian brain, including neuronal differentiation and growth, synapse formation and plasticity, and higher cognitive functions. This Review summarizes some of the recent progress in understanding the cellular and molecular mechanisms underlying neurotrophin regulation of neural circuits. The focus of the article is on BDNF, as this is the most widely expressed and studied neurotrophin in the mammalian brain.

Neurotrophin regulation of neural circuit development and function

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.

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Physiology and Pathophysiology of Purinergic Neurotransmission

http://www2.neuroscience.umn.edu/eanwebsite/PDF%20GJClub/Trends%20Neurosci%2032%20421%202009.pdf

Tripartite synapses: astrocytes process and control synaptic information

https://www.cell.com/trends/neurosciences/pdf/S0166-2236(03)00266-2.pdf

New roles for astrocytes: redefining the functional architecture of the brain

ATP Released by Astrocytes Mediates Glutamatergic Activity-Dependent Heterosynaptic Suppression

Repetitive correlated activation of pre- and postsynaptic neurons induced long-term potentiation (LTP) of synaptic transmission among hippocampal neurons grown on a layer of astrocytes (mixed cultures) but not among neurons cultured in glial conditioned medium. Supplement of d-serine, an agonist for the glycine-binding site of N-methyl-d-aspartate (NMDA) receptors, enhanced NMDA receptor activation and enabled LTP induction in glial conditioned medium cultures. The induction of LTP in both mixed cultures and hippocampal slices was suppressed by NMDA receptor antagonists, glycine-binding-site blockers of NMDA receptors, or an enzyme that degrades endogenous d-serine. By providing extracellular d-serine that facilitates activation of NMDA receptors, astrocytes thus play a key role in long-term synaptic plasticity.

/pdf/contribution-of-astrocytes-to-hippocampal-long-term-1t1j6qf3zz.pdf

Contribution of astrocytes to hippocampal long-term potentiation through release of d-serine

Astrocyte glutamate release can modulate synaptic activity and participate in brain intercellular signaling. P2X7receptors form large ion channels when activated by ATP or other ligands. Here we show that P2X7 receptors provide a route for excitatory amino acid release from astrocytes. Studies were performed using murine cortical astrocyte cultures. ATP produced an inward current in patch-clamped astrocytes with properties characteristic of P2X7 receptor activation: the current was amplified in low divalent cation medium, blocked by pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), and more potently activated by 3′-O-(4-benzoyl)benzoyl ATP (BzATP) than by ATP itself. Measurement of current reversal potentials showed the relative BzATP-induced permeabilities to different substrates to be Na+, 1 > Cl−, 0.34 >N-methyl-d-glucamine, 0.27 >l-glutamate, 0.15 ≈ d-aspartate, 0.16. Astrocytes exposed to BzATP also became permeable to Lucifer yellow, indicating a large channel opening. Release of l-glutamate and d-aspartate through P2X7 channels was confirmed using radiolabeled tracers. As with the inward current, release of glutamate and d-aspartate was induced by BzATP more potently than ATP, amplified in Ca2+/Mg2+-free medium, and blocked by PPADS or oxidized ATP. Efflux through P2X7channels is a previously unrecognized route of ligand-stimulated, nonvesicular astrocyte glutamate release.

https://www.jneurosci.org/content/jneuro/23/4/1320.full.pdf

P2X7 Receptor-Mediated Release of Excitatory Amino Acids from Astrocytes

https://www.cell.com/neuron/pdf/S0896-6273(06)00214-5.pdf

Activity-induced rapid synaptic maturation mediated by presynaptic cdc42 signaling.

Niemann-Pick disease type C (NPC) is a deadly neurodegenerative disease often caused by mutation in a gene called NPC1, which results in the accumulation of unesterified cholesterol and glycosphingolipids in the endosomal-lysosomal system. Most studies on the mechanisms of neurodegeneration in NPC have focused on neurons. However, the possibility also exists that NPC1 affects neuronal functions indirectly by acting on other cells that are intimately interacting with neurons. In this study, using a heterotypic neuron-glia coculture system, we found that wild-type neurons cultured on a layer of NPC1-/- astrocytes showed decreased neurite growth compared with those cultured on wild-type astrocytes. RT-PCR and immunohistochemical assessments showed significantly lower expression of neurosteroid enzymes and StAR (steroidogenic acute regulatory protein) in NPC1-/- astrocyte cultures than in wild-type cultures. Furthermore, a reduced level of estradiol was measured from both astrocyte culture medium and whole brains from NPC1-/- mice. Administration of 17 beta-estradiol to neonatal NPC1-/- mice significantly delayed the onset of neurological symptoms, increased Purkinje cell survival, and extended the animals' life span. Our findings suggest that astrocyte dysfunction contributes to the neurodegeneration of NPC and estradiol treatment may be useful in ameliorating progression of the disease. (C) 2007 Wiley-Liss, Inc.

Yiren Chen

Papers

ATP Released by Astrocytes Mediates Glutamatergic Activity-Dependent Heterosynaptic Suppression

Contribution of astrocytes to hippocampal long-term potentiation through release of d-serine

P2X7 Receptor-Mediated Release of Excitatory Amino Acids from Astrocytes

Activity-induced rapid synaptic maturation mediated by presynaptic cdc42 signaling.

Decreased estradiol release from astrocytes contributes to the neurodegeneration in a mouse model of Niemann-Pick disease type C.