The tripartite synapse: roles for gliotransmission in health and disease.

Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania, School of Medicine Philadelphia, PA 19104, USA.
Trends in Molecular Medicine (Impact Factor: 10.11). 03/2007; 13(2):54-63. DOI: 10.1016/j.molmed.2006.12.005
Source: PubMed

ABSTRACT In addition to being essential supporters of neuronal function, astrocytes are now recognized as active elements in the brain. Astrocytes sense and integrate synaptic activity and, depending on intracellular Ca(2+) levels, release gliotransmitters (e.g. glutamate, d-serine and ATP) that have feedback actions on neurons. Recent experimental results have raised the possibility that quantitative variations in gliotransmission might contribute to disorders of the nervous system. Here, we discuss targeted molecular genetic approaches that have demonstrated that alterations in protein expression in astrocytes can lead to serious changes in neuronal function. We also introduce the concept of 'astrocyte activation spectrum' in which enhanced and reduced gliotransmission might contribute to epilepsy and schizophrenia, respectively. The results of future experimental tests of the astrocyte activation spectrum, which relates gliotransmission to neurological and psychiatric disorders, might point to a new therapeutic target in the brain.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The fine-tuning of synaptic transmission by astrocyte signaling is crucial to CNS physiology. However, how exactly astroglial excitability and gliotransmission are affected in several neuropathologies, including epilepsy, remains unclear. Here, using a chronic model of temporal lobe epilepsy (TLE) in rats, we found that astrocytes from astrogliotic hippocampal slices displayed an augmented incidence of TTX-insensitive spontaneous slow Ca(2+) transients (STs), suggesting a hyperexcitable pattern of astroglial activity. As a consequence, elevated glutamate-mediated gliotransmission, observed as increased slow inward current (SICs) frequency, up-regulates the probability of neurotransmitter release in CA3-CA1 synapses. Selective blockade of spontaneous astroglial Ca(2+) elevations as well as the inhibition of purinergic P2Y1 or mGluR5 receptors relieves the abnormal enhancement of synaptic strength. Moreover, mGluR5 blockade eliminates any synaptic effects induced by P2Y1R inhibition alone, suggesting that the Pr modulation via mGluR occurs downstream of P2Y1R-mediated Ca(2+) -dependent glutamate release from astrocyte. Our findings show that elevated Ca(2+) -dependent glutamate gliotransmission from hyperexcitable astrocytes up-regulates excitatory neurotransmission in epileptic hippocampus, suggesting that gliotransmission should be considered as a novel functional key in a broad spectrum of neuropathological conditions. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Glia 05/2015; DOI:10.1002/glia.22817 · 6.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecular machinery on the scale of nanoscopic astroglial compartments remains a challenge. Here we briefly summarize the current knowledge regarding the cellular organisation of astroglia in the synaptic microenvironment and discuss molecular mechanisms potentially involved in use-dependent astroglial morphogenesis. We also discuss recent observations concerning morphological astroglial plasticity, the respective monitoring methods, and some of the newly emerging techniques that might help with conceptual advances in the area. GLIA 2015. © 2015 The Authors. Glia Published by Wiley Periodicals, Inc.
    Glia 03/2015; DOI:10.1002/glia.22821 · 6.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: d-serine is a coagonist of N-methyl-d-aspartate (NMDA) subtype of glutamate receptor and plays a role in regulating activity-dependent synaptic plasticity. In this study, we examined the mechanism by which extracellular ATP triggers the release of d-serine from astrocytes and discovered a novel Ca2+-independent release mechanism mediated by P2X7 receptors (P2X7R). Using [3H] d-serine, which was loaded into astrocytes via the neutral amino acid transporter 2 (ASCT2), we observed that ATP and a potent P2X7R agonist, 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate (BzATP), stimulated [3H]D-serine release and that were abolished by P2X7R selective antagonists and by shRNAs, whereas enhanced by removal of intracellular or extracellular Ca2+. The P2X7R-mediated d-serine release was inhibited by pannexin-1 antagonists, such as carbenoxolone (CBX), probenecid (PBN), and 10Panx-1 peptide, and shRNAs, and stimulation of P2X7R induced P2X7R-pannexin-1 complex formation. Simply incubating astrocytes in Ca2+/Mg2+-free buffer also induced the complex formation, and that enhanced basal d-serine release through pannexin-1. The P2X7R-mediated d-serine release assayed in Ca2+/Mg2+-free buffer was enhanced as well, and that was inhibited by CBX. Treating astrocytes with general protein kinase C (PKC) inhibitors, such as chelerythrine, GF109203X, and staurosporine, but not Ca2+-dependent PKC inhibitor, Gö6976, inhibited the P2X7R-mediated d-serine release. Thus, we conclude that in astrocytes, P2X7R-pannexin-1 complex formation is crucial for P2X7R-mediated d-serine release through pannexin-1 hemichannel. The release is Ca2+-independent and regulates by a Ca2+-independent PKC. The activated P2X7R per se is also functioned as a permeation channel to release d-serine in part. This P2X7R-mediated d-serine release represents an important mechanism for activity-dependent neuron-glia interaction. GLIA 2015
    Glia 01/2015; 63(5). DOI:10.1002/glia.22790 · 6.03 Impact Factor