The tripartite synapse: Roles for gliotransmission in health and disease
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.
- SourceAvailable from: Jin-Hui Wang
Frontiers in Cellular Neuroscience 08/2015; 9(320):1-17. · 4.18 Impact Factor
- "+ signals was positively correlated to spike frequency , and the duration of Ca 2+ signals was correlated with spike number . So , Ca 2+ levels in a neuron indicated its response strength in vivo ( Petersen et al . , 2005 ; Yaksi and Friedrich , 2006 ; Moreaux and Laurent , 2007 ) . The activity of the astrocytes also altered their Ca 2+ signals ( Halassa et al . , 2007 ) . The synchrony of Ca 2+ signals among cell pairs was analyzed by correlation coefficients to represent their activity synchrony ( Hirase et al . , 2004 ; Takata and Hirase , 2008 ; Golshani et al . , 2009 ) ."
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- "While astrocytes are not electrically excitable like neurons, one mode of prominent activity of astrocytes is the release of calcium from internal stores following activation of a variety of G-protein coupled receptors. Many groups have hypothesized that calcium signaling in astrocytes underlies the release of many signaling molecules, termed 'gliotransmitters', which can directly impact neural circuit excitability . While dynamic calcium transients have been readily observed in the somas and proximal thick processes of astrocytes maintained in culture and/or in brain slices prepared from very young animals, synthetic calcium-indicating dyes have been difficult to deliver in either adult or sclerotic tissue. "
ABSTRACT: Temporal lobe epilepsy (TLE) is a devastating seizure disorder that is often caused by status epilepticus (SE). Temporal lobe epilepsy can be very difficult to control with currently available antiseizure drugs, and there are currently no disease-modifying therapies that can prevent the development of TLE in those patients who are at risk. While the functional changes that occur in neurons following SE and leading to TLE have been well studied, only recently has research attention turned to the role in epileptogenesis of astrocytes, the other major cell type of the brain. Given that epilepsy is a neural circuit disorder, innovative ways to evaluate the contributions that both neurons and astrocytes make to aberrant circuit activity will be critical for the understanding of the emergent network properties that result in seizures. Recently described approaches using genetically encoded calcium-indicating proteins can be used to image dynamic calcium transients, a marker of activity in both neurons and glial cells. It is anticipated that this work will lead to novel insights into the process of epileptogenesis at the network level and may identify disease-modifying therapeutic targets that have been missed because of a largely neurocentric view of seizure generation following SE. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015. Published by Elsevier Inc.Epilepsy & Behavior 07/2015; DOI:10.1016/j.yebeh.2015.05.002 · 2.06 Impact Factor
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- "This pathological astrocyte-neuron communication could be the key mechanism that determines seizure recurrence and epilepsy chronicity through the maintenance of an elevated glutamatergic tone. This work provides direct evidence of the pathophysiological role of astrocytes, demonstrating that altered astroglial signaling has severe effects on synaptic transmission, and supporting the idea that astroglial hyper or hypoactivation could take part in a broad spectrum of neurological disorders, as previously suggested (Devinsky et al., 2013; Halassa et al., 2007; Seifert et al., 2006). These findings support the pivotal role of astroglial Ca 21 signal and gliotransmission in pathophysiological conditions , providing a new perspective to advance toward understanding the biology of epilepsy and other brain diseases. "
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; 63(9). DOI:10.1002/glia.22817 · 6.03 Impact Factor