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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: 9.45). 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.

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    • "i increases in astrocytes in response to the activity of adjacent astrocytes and neurons ; ( 2 ) elicited [ Ca 2+ ] i elevation induces release of gliotransmitters ( Halassa et al . , 2007 ; Oya et al . , 2013 ; Khakh and McCarthy , 2015 ) . Although the exact mechanisms of gliotransmission are unclear , recent studies have partially revealed the release mechanisms of glutamate , D - serine , and ATP in astrocytes ( Figure 2 ; Gucek et al . , 2012 ; Li et al . , 2013 ) ."
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    ABSTRACT: Astrocytes comprise a large population of cells in the brain and are important partners to neighboring neurons, vascular cells, and other glial cells. Astrocytes not only form a scaffold for other cells, but also extend foot processes around the capillaries to maintain the blood–brain barrier. Thus, environmental chemicals that exist in the blood stream could have potentially harmful effects on the physiological function of astrocytes. Although astrocytes are not electrically excitable, they have been shown to function as active participants in the development of neural circuits and synaptic activity. Astrocytes respond to neurotransmitters and contribute to synaptic information processing by releasing chemical transmitters called “gliotransmitters.” State-of-the-art optical imaging techniques enable us to clarify how neurotransmitters elicit the release of various gliotransmitters, including glutamate, D-serine, and ATP. Moreover, recent studies have demonstrated that the disruption of gliotransmission results in neuronal dysfunction and abnormal behaviors in animal models. In this review, we focus on the latest technical approaches to clarify the molecular mechanisms of gliotransmitter exocytosis, and discuss the possibility that exposure to environmental chemicals could alter gliotransmission and cause neurodevelopmental disorders.
    Preview · Article · Jan 2016 · Frontiers in Neuroscience
    • "O ver the last decade the glial cell astrocytes, beyond their broad control of brain tissue homeostasis and metabolism , have been recognized to regulate neuronal network activities (Araque et al., 2001; Carmignoto, 2000; Halassa et al., 2007; Haydon and Carmignoto, 2006; Perea et al., 2009; Volterra and Meldolesi, 2005). Indeed, astrocytes can modulate synaptic transmission and contribute to important phenomena in brain function thanks to a dynamic interaction with neurons that is finely regulated in time and space (Araque et al., 2014). "
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    ABSTRACT: Studies over the last decade provided evidence that in a dynamic interaction with neurons glial cell astrocytes contribut to fundamental phenomena in the brain. Most of the knowledge on this derives, however, from studies monitoring the astrocyte Ca(2+) response to glutamate. Whether astrocytes can similarly respond to other neurotransmitters, including the inhibitory neurotransmitter GABA, is relatively unexplored. By using confocal and two photon laser-scanning microscopy the astrocyte response to GABA in the mouse somatosensory and temporal cortex was studied. In slices from developing (P15-20) and adult (P30-60) mice, it was found that in a subpopulation of astrocytes GABA evoked somatic Ca(2+) oscillations. This response was mediated by GABAB receptors and involved both Gi/o protein and inositol 1,4,5-trisphosphate (IP3 ) signalling pathways. In vivo experiments from young adult mice, revealed that also cortical astrocytes in the living brain exibit GABAB receptor-mediated Ca(2+) elevations. At all astrocytic processes tested, local GABA or Baclofen brief applications induced long-lasting Ca(2+) oscillations, suggesting that all astrocytes have the potential to respond to GABA. Finally, in patch-clamp recordings it was found that Ca(2+) oscillations induced by Baclofen evoked astrocytic glutamate release and slow inward currents (SICs) in pyramidal cells from wild type but not IP3 R2(-/-) mice, in which astrocytic GABAB receptor-mediated Ca(2+) elevations are impaired. These data suggest that cortical astrocytes in the mouse brain can sense the activity of GABAergic interneurons and through their specific recruitment contribut to the distinct role played on the cortical network by the different subsets of GABAergic interneurons. GLIA 2015.
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    • "For instance, the neural activity is composed of an interplay between excitation and inhibition where the cerebral blood flow (CBF) dynamics is an essential element as it reflects nutriments supplies such as oxygen and glucose. Synaptic transmission [1] [2] [15] [25] [39] and neural activity [13] [16] [27] are regulated by neurotransmitters, ions and molecules. Broadly speaking, at the microscopic scale, the presynaptic neuron releases neurotransmitters in the synaptic cleft which may bind to postsynaptic neuron receptors. "
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    ABSTRACT: The investigation of the neuronal environment allows us to better understand the activity of a cerebral region as a whole. The recent experimental evidences of the presence of transporters for glutamate and GABA in both neuronal and astrocyte compartments raise the question of the functional importance of the astrocytes in the regulation of the neuronal activity. We propose a new computational model at the mesoscopic scale embedding the recent knowledge on the physiology of neuron and astrocyte coupled activities. The neural compartment is a neural mass model with double excitatory feedback, and the glial compartment focus on the dynamics of glutamate and GABA concentrations. Using the proposed model, we first study the impact of a deficiency in the reuptake of GABA by astrocytes, which implies an increase in GABA concentration in the extracellular space. A decrease in the frequency of neural activity is observed and explained from the dynamics analysis. Second, we investigate the neuronal response to a deficiency in the reuptake of Glutamate by the astrocytes. In this case, we identify three behaviors : the neural activity may either be reduced, or enhanced or, alternatively, may experience a transient of high activity before stabilizing around a new activity regime with a frequency close to the nominal one. After translating theoretically the neuronal excitability modulation using the bifurcation structure of the neural mass model, we state the conditions on the glial feedback parameters corresponding to each behavior.
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