Search tips
Search criteria 


Logo of pursigspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
Purinergic Signal. 2008 December; 4(4): 339–346.
Published online 2008 June 21. doi:  10.1007/s11302-008-9115-1
PMCID: PMC2583203

ATP signalling in epilepsy


This paper focuses on a role for ATP neurotransmission and gliotransmission in the pathophysiology of epileptic seizures. ATP along with gap junctions propagates the glial calcium wave, which is an extraneuronal signalling pathway in the central nervous system. Recently astrocyte intercellular calcium waves have been shown to underlie seizures, and conventional antiepileptic drugs have been shown to attenuate these calcium waves. Blocking ATP-mediated gliotransmission, therefore, represents a potential target for antiepileptic drugs. Furthermore, while knowledge of an antiepileptic role for adenosine is not new, a recent study showed that adenosine accumulates from the hydrolysis of accumulated ATP released by astrocytes and is believed to inhibit distant synapses by acting on adenosine receptors. Such a mechanism is consistent with a surround-inhibitory mechanism whose failure would predispose to seizures. Other potential roles for ATP signalling in the initiation and spread of epileptiform discharges may involve synaptic plasticity and coordination of synaptic networks. We conclude by making speculations about future developments.

Keywords: Astrocytes, ATP, Epilepsy, Gliotransmission, Seizure


Purinergic signalling, defined as adenosine 5′-triphosphate (ATP) released as a transmitter or cotransmitter acting extracellularly on pre- and pos-tjunctional membranes at neuroeffector junctions and synapses, was first described over 35 years ago [1]. Although the idea was initially received with scepticism, purinergic signalling is now widely accepted as many physiological processes incorporate this mechanism [2]. Consequently, purinergic pathophysiology would expectedly play a role in the pathogenesis of disease, thereby giving clues to potential therapeutics. The earliest disease processes believed to incorporate a purinergic basis included pain [3] and migraine [4]. At the present time, a large and growing body of evidence suggests purinergic drug targets may improve a growing list of diseases. For example, clopidogrel, the P2Y12 inhibitor, the first of such drugs, is already in use for stroke and thrombosis [5] and, it is hoped, will be a forerunner among many.

Many neurons release ATP as a co-transmitter, and this serves as an activity-dependent signal which evokes a response in astrocytes, Schwann cells and oligodendrocytes that express P2 receptors. Astrocytes can respond by strengthening the synapse, for example by releasing both glutamate and ATP into the synaptic cleft. Schwann cells at the neuromuscular junction respond to axonal ATP release following an action potential with a rise in intracellular Ca2+. Recognition of a passing action potential is key in the development of oligodendrocyte progenitors into oligodendrocytes [6].

Earlier studies suggestive of a role for purinergic signalling in epilepsy included the finding that seizure-prone mice have increased extracellular ATP levels, possibly owing to decreased brain ATPase activity [7]. Moreover, microinjection of ATP analogues into the rodent prepiriform cortex was shown to cause generalised motor seizures [8]. Thirdly, it was found that P2X7 receptors are upregulated by 80% in hippocampi of pilocarpine-induced chronic epileptic rats, as shown by fluorimetric, immunohistochemical and Western-blotting techniques [9].

Meanwhile, a role for adenosine in epilepsy, particularly status epilepticus, has long been suggested [10]. Recent studies have confirmed such a role and attributed A1 receptor activation to the observed antiepileptic effects [11, 12]. On the other hand, Zeraati et al. [13] elegantly showed that A2A receptors in the CA1 hippocampal region have the opposite effect to A1 receptors in a piriform cortex kindling model.

Adenosine receptors are believed to play a role in presynaptic modulation of neuronal excitability and epileptogenesis [14], although the expression and function of adenosine receptors in various models of epilepsy is controversial. While Angelatou et al. [15] report upregulation of purinergic P1 receptors in the neocortex of patients with temporal lobe epilepsy, other groups report receptor downregulation [1618]. Purinergic mechanisms in epilepsy have previously been described in the context of adenosine as an antiepileptic agent [19]. Therein, adenosine-releasing grafts have been shown to suppress both seizures [20] and epileptogenesis [21] in kindling models of epilepsy. Furthermore, adenosine kinase inhibition may also promote increased levels of extracellular adenosine thereby providing antiepileptic effects [22].

Indeed, other adenosine-mediated pharmacological strategies are being actively explored, and exciting studies are underway. Additionally, pH variation under respiratory control has been shown to affect cortical excitability in an ATP- and adenosine-dependent manner [23] and this may be relevant to the pathophysiology of epileptic seizures, for example, those in childhood absence epilepsy. In this paper we focus on recent developments in the role of ATP signalling in epilepsy.

ATP as a neurotransmitter and gliotransmitter

ATP released by neurons and glia has several functions including regulation of synaptic transmission both directly and through glia, responses to injury and inflammation, pain, myelination and neurogenesis (for review please see [24]). Additionally, ATP satisfies all of Dale’s criteria as a neurotransmitter. Firstly, it is released from synaptosomes in the cerebral cortex, hypothalamus, medulla and other parts of the central nervous system (CNS) with presynaptic localisation in vesicles with high intravesicular concentration [25]. Secondly, upon a physiologically relevant stimulus, ATP is released by a SNARE-dependent mechanism [26]. However, this mechanism is controversial since astrocytic ATP has recently been shown to be released by lysosome exocytosis [27, 28]. Thirdly, it acts with specificity on P2X ligand-gated ion channel receptors and P2Y G-protein-coupled receptors. For a recent review of purinergic receptor expression patterns and functions please see [29]. Finally, ATP incorporates an inactivation system as it is rapidly broken into adenosine by the ectoenzymes ectoATP diphosphohydrolase and ecto-phosphodiesterases/ecto-nucleotide pyrophosphatases [25].

The glial calcium wave

Elevations in intracellular calcium propagate between astroglial cells as the calcium wave [3032]. This extraneural signal transduction mechanism is crucial to glial homeostasis, and increased intracellular Ca2+ leads to a variety of responses including growth, differentiation and release of neuroactive mediators [33, 34]. Calcium waves are believed to be the mechanism of long-distance glial signalling in the CNS as they have been observed to travel more than 500 µm at a velocity of 14 µm/s in culture [35].

Key to the propagation of these calcium waves is ATP released by astrocytes as the calcium wave propagates, and this is facilitated by gap junctions permeable to Ca2+ ions [36, 37]. Calcium waves can be evoked by applying ATP, which acts on P2 receptors, the blockade of which attenuates calcium waves [38]. P2Y1 and P2Y2 receptors are both necessary and sufficient for the calcium-wave propagation, and P2Y2 receptors propagate calcium waves faster and further than P2Y1 receptors [39]. In addition, a key role for P2X7 receptors is established as well as possibly contributory roles for P2X2, P2X4, P2X5, P2Y2, P2Y4 and P2Y14 based on agonist preferences [40]. Interesting quantitative models of purinergic junctional transmission of calcium waves have been conducted on astrocyte networks [41, 42].

Astrocytes modulate neurotransmission

Astrocytes have been shown to directly influence neurotransmission at synapses through the release of glutamate [43] and D-serine [44]. The controlled release of neurotransmitters (or equally, gliotransmitters that modulate neurotransmission) at the synaptic cleft implies and bestows a protagonist role on astrocytes in the tripartite synapse [45].

Early studies indicated that, independent of whether the synapse is excitatory or inhibitory, astrocyte stimulation decreased postsynaptic current responses during synaptic activity [46]. Additionally, miniature postsynaptic current responses were enhanced in frequency but not amplitude [47]. Taken together, these two findings suggest glutamate released by astrocytes modulates presynaptic metabotropic glutamate receptors according to the former finding and NMDA receptors according to the latter. Further studies showed that NMDA receptor-mediated synchrony of neuronal activity may be through modulation of either synaptic [48] or extrasynaptic receptors [49]. Conversely, activity-dependent astrocyte-mediated potentiation of GABAergic synapses has also been demonstrated, suggesting a crucial role in their modulation [50]. Somewhat unintuitively, astrocytic glutamate release is believed to underlie these effects, which are concordant with the findings of Newman and Zahs [51] who first demonstrated neuromodulatory glial control in the retina. Indeed, an interesting recent study has characterised glial neuromodulatory activity down to the level of a single synapse [52].

Furthermore, bidirectional exchange of glutamatergic neurotransmission between astrocytes and hippocampal CA1 pyramidal neurons was elegantly demonstrated in situ [53]. Similarly, Ca2+ oscillations in astrocytes have been shown to be induced by neuronal firing [54], suggestive of perisynaptic activation of glial cells. In addition, larger-scale intercellular astrocytic calcium signalling is also believed to be regulated by synaptic activity [55]. Indeed, by virtue of the glial calcium wave, astrocytes have been put forth as important cellular elements involved in the bidirectional processing of synaptic information [56].

All in all, glial calcium waves may either be propagated by “carrying forward” gliotransmission or synaptic activity and may manifest this activation by further influencing neurotransmission or propagating a calcium wave, with a vast array of effects. Gliotransmission combined with glial modulation of neurotransmission is thus suggestive of active bidirectional communication [57]. Calcium waves have therefore been put forth as a mechanism that encodes and transmits information to harmonise neuronal electrical activity, possibly even involving large volumes of activation in the human brain [45]. Therefore, we hypothesize that calcium waves might propagate and therefore synchronise epileptiform activity, as shown in Fig. 1.

Fig. 1
Calcium wave-mediated synchronisation of neuronal spiking. At a simplified glutamatergic synapse when neurotransmission occurs (1), glutamate acts on metabotropic glutamate receptors on astrocytes (2), promoting astrocytic glutamate release (3) which ...

The astrocytic basis of epilepsy

Epilepsy is characterised by hypersynchronous neuronal firing although the mechanisms that initiate seizures are largely unknown. As a result, antiepileptic drugs (AEDs) simply provide symptomatic relief as they fall into three broad categories—drugs that promote GABAergic neurotransmission (e.g. barbituates, benzodiazepines, vigabatrin and tiagabine); drugs that decrease glutamatergic neurotransmission (e.g. topiramate and felbamate); or drugs that block voltage-gated Na+ channels (e.g. phenytoin, carbamazepine and lamotrigine) to attenuate high-frequency action potentials in both amplitude and rate of rise [58]. However, in doing so AEDs compromise normal neural function, often with severe side effects [58]. Furthermore, despite a wide variety of AEDs, drug-resistant epilepsy, which is often focal, remains a debilitating problem which often responds only to neurosurgery such as temporal lobe resection in temporal lobe epilepsy, corticectomy or vagus nerve stimulation, which are not without considerable risks and costs.

The cellular correlate of interictal epileptiform activity is the paroxysmal depolarisation shift (PDS)—abnormal prolonged depolarisations with repetitive spiking induced by ionotropic glutamate receptor activation which is thought to drive groups of neurons into hypersynchronous bursting [59]. Astrocytes effect glutamate release upon a Ca2+ and SNARE-dependent mechanism [60, 61]. Physiologically, this typically follows increased intracellular Ca2+ levels resulting from glial communication via the calcium wave (see below). This phenomenon has been pharmacologically demonstrated by activation of type I metabotropic glutamate receptors (mGluRs) by their agonist dihydroxyphenylglicine (DHPG), by intracellular injection of IP3 or by increasing intracytoplasmic Ca2+ levels by photolysis of caged Ca2+ [62]. Importantly, glutamate release from astrocytes has been demonstrated to play a key role in the control of synaptic strength and is based upon stimulation of astrocytic P2Y1 receptors based on neuronal activity [63].

The role of this astrocytic glutamate release in triggering PDSs was characterised by Tian et al [64]. Patched CA1 pyramidal neurons from rat hippocampal slices were found to undergo PDSs when exposed to the epileptogenic K+ channel blocker 4-aminopyridine (4-AP), and the majority (70–90%) of these PDSs were insensitive to TTX, suggesting PDSs can be triggered sans action potentials. Furthermore, photolysis of caged Ca2+ in astrocytes but not neurons evoked PDSs in a mechanism consistent with Ca2+-dependent glutamate release. In vivo studies using two-photon imaging of exposed cortex of adult mice during seizures induced by the proeplileptic drug 4-AP showed that three AEDs—valproate, gabapentin and phenytoin—decreased 4-AP-induced Ca2+ signalling (by 69.7, 55.6 and 45.5% respectively) and ATP-induced Ca2+ signalling (by 64.9, 53.8 and 23.8% respectively). A problem with all studies of experimental epilepsy is how closely they match the human disease [65]. This study in particular was controversial as Fellin et al. [66] showed that astrocytic glutamate is not necessary to generate epileptiform activity. Moreover, a recent study has challenged the capability of astrocytes to release glutamate [67, 68].

Notwithstanding, astrocytic glutamate release may explain how glial scarring underlies post-traumatic epilepsy and hippocampal sclerosis leads to mesiotemporal epilepsy. Furthermore, it remains possible that blocking astrocytic glutamate release, for example by inhibiting components of the astrocytic calcium wave, may decrease seizures or prevent their spreading.

Novel antiepileptic drug targets

The mechanism of astrocytic calcium waves is reviewed above, and we propose that this is the initiating event of epileptic seizures because they could theoretically carry-over neuronal excitability from one set of recently activated neurons to another dormant set of neurons. Such a model would spatiotemporally synchronise the second group to fire unexpectedly and in harmonic synergy to the first set which is the neurophysiological hallmark of epileptiform spiking. Secondly, astrocytic calcium-wave signalling mediates interastrocytic excitation, which is the decisive final step prior to astrocytic glutamate release [69], which then acts on neurons to evoke EPSPs [64]. Therefore, we propose that blocking the astrocytic calcium wave represents a proximal, albeit relatively unexplored, drug target for the treatment of focal epilepsy.

From analysis of the models of astrocytic calcium-wave signalling, two obvious drug targets are apparent—gap junctions and P2Y receptors. The role of gap-junction signalling in epilepsy is still unclear [70]. While inhibiting gap-junction signalling has already been shown to have antiepileptic properties [71, 72], there is evidence that ionic conductance through gap junctions only partly accounts for ionic buffering [73]. However, the gap-junction protein Cx43 has been shown to modulate both astrocytic P2Y1 receptor expression levels [74] and pharmacological function [75]. Moreover, ATP efflux from Cx43 hemichannels has recently been demonstrated [76], further expanding the scope of purinergic signalling in gliotransmission. Therefore, the role of gap junctions in propagating the calcium wave, their interplay with P2 receptors, and whether this is the substrate of their antiepileptic effect when inhibited, remains to be fully determined. In the interim, purinergic receptor modulation may hold promise in novel antiepileptic drugs indicated for focal or drug resistant epilepsy.

Moreover, we believe astrocytic purinergic signalling has a more significant role in influencing the synaptic plasticity which perpetuates epilepsy, since ATP is co-released with glutamate in a neuronal activity-dependent manner [77]. We hypothesize that increased extracellular ATP levels promote organisation of neurons into functional assemblies, especially since ATP has been shown to do the same in development prior to synaptogenesis [78]. This takes prominence since altered synaptic plasticity is believed to lead to neuronal circuits which are strengthened by long-term potentiation-like mechanisms [79], and although preventing synaptic remodelling in epilepsy is a relatively unexplored area, we believe our proposed therapy will decrease long-term remodelling in the epileptic brain. Moreover, since P2 receptor activation is associated with astrogliosis [80], P2 receptor inhibition would be expected to prevent the formation of an epileptogenic focus after brain injury.

Glial calcium waves do, however, represent a complex target owing to a variety of direct and indirect functions. Firstly, calcium-wave signalling underlies glial regulation of cerebral microvasculature and metabolism which may be either proepileptic or antiepileptic [81, 82]. Secondly, calcium-wave signalling may occur either as a cause or an effect of neurotransmission, and a successful antiepileptic strategy would entail targeting only those with a putatively causal role in excitatory neurotransmission. Another source of complexity is the variation in models of calcium-wave signalling (reviewed in [83]), whose underlying mechanisms differ between brain regions. Haas et al. [84] elegantly showed that activity-dependent ATP release propagates within mouse neocortex independent from astrocytic calcium waves, thereby raising the possibility that calcium-wave signalling may have further anatomical variations. However, this is not necessarily a setback as such variation may offer greater specificity in treating different types of seizures as specific anatomical or pharmacological targets are identified.

Taken together, it can be argued that the effects of attenuating glial calcium waves on neuronal networks in the human brain may be hard to predict. However, we argue that the same can be said of inhibiting neuronal firing en masse as a therapeutic strategy in epilepsy. The multitude of functional roles and anatomical variation of gliotransmission is analogous to the nonspecific anatomical and functional variations of neurotransmission (e.g. excitatory versus inhibitory neurotransmission, reductio ad absurdum). In other words, as more is learned about the molecular pathophysiology of the PDS, we simply offer modulation of gliotransmission as an adjunct to inhibiting neurotransmission as a novel antiepileptic approach.

Coordinating synaptic networks

Although ATP acting on P2 receptors is excitatory as it opens cation channels and as it acts on neuronal P2X7 receptors whose clustering in presynaptic densities is suggestive of positively modulating glutamate release [85], astrocyte-released ATP is actually inhibitory to neurons [86]. The mechanism for this is that ATP is rapidly broken down into adenosine by ectonucleotidases (E-NTPDase, E-NPP, alkaline phosphatises, and ecto-5′ nucleotidase; reviewed by Zimmermann [87]), which is inhibitory to neurons [88].

Using an innovative transgenic mouse model expressing a dominant negative SNARE domain to selectively block astrocytic ATP release, Pascual et al. [89] elegantly showed that astrocytic purinergic signalling coordinates synaptic networks. As alluded to above, ATP is released in an activity-dependent mechanism in response to neuronal firing and is hydrolysed extracellularly to adenosine. This accumulated adenosine diffuses and tonically suppresses synaptic transmission at distant sites. The authors suggest that such a mechanism enhances the dynamic range for long-term potentiation and mediated activity-dependent heterosynaptic depression, which then provides a pathway for synaptic crosstalk.

Several issues pertaining to epilepsy arise from this excellent paper. Prima facie, as pathological synaptic transmission underlies epilepsy, awry purinergic signalling is a legitimate possibility. In addition to the authors’ description of a role in crosstalk between distant synapses, we propose another role: surround inhibition (Fig. 2). Accumulated adenosine is mediating collateral inhibition of adjacent neurons after neuronal activity, thereby seeking to enhance the signal by reducing background noise.

Fig. 2
Activity-dependent ATP release from astrocytes mediates surround inhibition. The synapse in the centre of the figure is strengthened by astrocytic glutamate release. Adjacent neurons are inhibited when ATP released upon neuronal activity is broken down ...

Reducing this background noise would imply that lower concentrations of glutamate would be necessary for signal transduction, which in turn may prevent neuronal cell death by preventing NMDA receptor overstimulation. A surround inhibitory mechanism, although traditionally ascribed to GABAergic neurons, prevents seizure propagation [90], and its failure would provoke epileptic seizures.

The function of ATP can vary, and it cannot be easily predicted if excitation or inhibition will prevail. While it is possible that there may be a balance, the two functions may also display spatial and temporal separation, as a corollary to Pascual et al. [89]. A temporal separation is more obvious as ectonucleotidases rapidly convert ATP to adenosine. Therefore, any excitatory role of ATP would be immediate and short-acting. Conversely, as the authors conjecture, a spatial separation pattern would emerge secondary to this owing to preferential diffusion of adenosine beyond the synaptic bouton in question leading to a widespread inhibitory function. Based on this model, more ATP may be better in producing more inhibitory adenosine although there is a risk of triggering pathological glial calcium waves [37] during their brief excitatory role.

Other pathological depolarisation phenomena

Two different mechanisms exist that perpetuate secondary injury in the CNS—peri-infarct depolarisations/hypoxic spreading depression [9193] and glial calcium-wave signalling [37]. Several superficial similarities exist between these two complex phenomena such as the rate of propagation of calcium waves (14 µm/s according to [35]) which is similar to spreading depression (15–35 µm/s) and the fact that both are blocked by purinergic receptor blockers. Therefore, while one paper suggests that astrocyte calcium waves are causal to spreading depression [94], another paper demonstrates that spreading depression can occur in the absence of calcium waves, for example when the bathing fluid is void of calcium [95]. Moreover, the metabolic toxins fluorocitrate [96] and fluoroacetate [97] that poison glia several hours before affecting neurons do not prevent spreading depression, but rather facilitate it (and glia at best play a passive role by attempting to stabilise extracellular K+ levels), bringing us closer to the original theory of spreading depression being a neuronal rather than a glial phenomenon [98]. All the same, there could be as-yet-undiscovered mechanisms that link these two, and until then, separate pharmacological interventions must be devised to address these two phenomena. However, since they both seek to perpetuate secondary injury, purinergic receptor blockade may be neuroprotective in the setting of acute neurotrauma [99, 100].


In summary, first we postulate that blockade of gliotransmission by purinergic modulation may improve epilepsy by decreasing synaptic strength across the tripartite synapse and by preventing synchronous ictal spread to distant sites. Secondly, we hypothesize that ATP released by astrocytes in response to neuronal activity is a source of surround inhibition to adjacent neurons. Such a model would both prevent propagation of seizures and also enhance neurotransmission by decreasing background noise. We hope our opinions are beneficial in the development of treatment strategies for epilepsy and other pathological depolarisation phenomena following neurotrauma.


Authors would like to thank Dr Gillian Knight for her help with the manuscript. A.K.’s work is supported by the Royal College of Physicians’ Wolfson Award. A.K. would like to thank Dr Franz Brunnhuber and Dr Rajan Saini for stimulating discussions.


Antiepileptic drugs
Adenosine 5′-triphosphate
Central nervous system
Paroxysmal depolarisation shift (PDS)


1. Burnstock G (1972) Purinergic nerves. Pharmacol Rev 24:509–581 [PubMed]
2. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797 [PubMed]
3. Burnstock G (1996) A unifying purinergic hypothesis for the initiation of pain. Lancet 347:1604–1605 [PubMed]
4. Burnstock G (1981) Pathophysiology of migraine: a new hypothesis. Lancet 317:1397–1399 [PubMed]
5. Hollopeter G, Jantzen H-M, Vincent D et al (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207 [PubMed]
6. Fields RD, Burnstock G (2006) Purinergic signalling in neuron-glia interactions. Nat Rev Neurosci 7(6):423–436 [PMC free article] [PubMed]
7. Wieraszko A, Seyfried TN (1989) Increased amount of extracellular ATP in stimulated hippocampal slices of seizure prone mice. Neurosci Lett 106:287–293 [PubMed]
8. Knutsen LJS, Murray TF (1997) Adenosine and ATP in epilepsy. In: Jacobson KA, Jarvis MF (eds) Purinergic approaches in experimental therapeutics. Wiley-Liss, New York, pp 423–447
9. Vianna EP, Ferreira AT, Naffah-Mazzacoratti MG et al (2002) Evidence that ATP participates in the pathophysiology of pilocarpine-induced temporal lobe epilepsy: fluorimetric, immunohistochemical, and Western blot studies. Epilepsia 43:227–229 [PubMed]
10. Young D, Dragunow M (1994) Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms. Neuroscience 58:245–261 [PubMed]
11. Avsar E, Empson RM (2004) Adenosine acting via A1 receptors, controls the transition to status epilepticus-like behaviour in an in vitro model of epilepsy. Neuropharmacology 47:427–437 [PubMed]
12. Vianna EP, Ferreira AT, Doná F et al (2005) Modulation of seizures and synaptic plasticity by adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats. Epilepsia 46:166–173 [PubMed]
13. Zeraati M, Mirnajafi-Zadeh J, Fathollahi Y et al (2006) Adenosine A1 and A2A receptors of hippocampal CA1 region have opposite effects on piriform cortex kindled seizures in rats. Seizure 15:41–48 [PubMed]
14. Malva JO, Silva AP, Cunha RA (2003) Presynaptic modulation controlling neuronal excitability and epileptogenesis: role of kainate, adenosine and neuropeptide Y receptors. Neurochem Res 28:1501–1515 [PubMed]
15. Angelatou F, Pagonopoulou O, Maraziotis T et al (1993) Upregulation of A1 adenosine receptors in human temporal lobe epilepsy: a quantitative autoradiographic study. Neurosci Lett 163:11–14 [PubMed]
16. Ekonomou A, Angelatou F, Vergnes M et al (1998) Lower density of A1 adenosine receptors in nucleus reticularis thalami in rats with genetic absence epilepsy. Neuroreport 9:2135–2140 [PubMed]
17. Ekonomou A, Pagonopoulou O, Angelatou F (2000) Age-dependent changes in adenosine A1 receptor and uptake site binding in the mouse brain: an autoradiographic study. J Neurosci Res 60:257–265 [PubMed]
18. Glass M, Faull RL, Bullock JY et al (1996) Loss of A1 adenosine receptors in human temporal lobe epilepsy. Brain Res 710:56–68 [PubMed]
19. Dragunow M (1988) Purinergic mechanisms in epilepsy. Prog Neurobiol 31:85–108 [PubMed]
20. Huber A, Padrun V, Déglon N et al (2001) Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy. Proc Natl Acad Sci USA 98:7611–7616 [PubMed]
21. Li T, Steinbeck JA, Lusardi T et al (2007) Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. Brain 130:1276–1288 [PubMed]
22. Boison D (2006) Adenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends Pharmacol Sci 27:652–658 [PubMed]
23. Dulla CG, Dobelis P, Pearson T et al (2005) Adenosine and ATP link PCO2 to cortical excitability via pH. Neuron 48:1011–1023 [PMC free article] [PubMed]
24. Fields D, Burnstock G (2006) Purinergic signalling in neuron-glial interactions. Nature Rev Neurosci 7:423–436 [PMC free article] [PubMed]
25. Lazarowski ER, Boucher RC, Harden TK (2003) Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol 64:785–795 [PubMed]
26. Volknandt W (2002) Vesicular release mechanisms in astrocytic signalling. Neurochem Int 41:301–306 [PubMed]
27. Pangrsic T, Potokar M, Stenovec M et al (2007) Exocytotic release of ATP from cultured astrocytes. J Biol Chem 282(39):28749–28758 [PubMed]
28. Zhang Z, Chen G, Zhou W et al (2007) Regulated ATP release from astrocytes through lysosome exocytosis. Nat Cell Biol 9(8):945–953 [PubMed]
29. Burnstock G (2007) Purine and pyrimidine receptors. Cell Mol Life Sci 64(12):1471–1483 [PubMed]
30. Charles AC, Merrill JE, Dirksen ER et al (1991) Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate. Neuron 6:983–992 [PubMed]
31. Cornell-Bell AH, Finkbeiner SM, Cooper MS et al (1990) Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247:470–473 [PubMed]
32. Nedergaard M (1994) Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263:1768–1771 [PubMed]
33. Vernadakis A (1996) Glia-neuron intercommunications and synaptic plasticity. Prog Neurobiol 49:185–214 [PubMed]
34. Scemes E, Giaume C (2006) Astrocyte calcium waves: what they are and what they do. Glia 54(7):716–725 [PMC free article] [PubMed]
35. Schipke CG, Boucsein C, Ohlemeyer C et al (2002) Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices. FASEB J 16:255–257 [PubMed]
36. Hassinger TD, Guthrie PB, Atkinson PB et al (1996) An extracellular signaling component in propagation of astrocytic calcium waves. Proc Natl Acad Sci USA 93:13268–13273 [PubMed]
37. Guthrie PB, Knappenberger J, Segal M et al (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19:520–528 [PubMed]
38. Cotrina ML, Lin JH, Alves-Rodrigues A et al (1998) Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci USA 95:15735–15740 [PubMed]
39. Gallagher CJ, Salter MW (2003) Differential properties of astrocyte calcium waves mediated by P2Y1 and P2Y2 receptors. J Neurosci 23(17):6728–6739 [PubMed]
40. Fumagalli M, Brambilla R, D’Ambrosi N et al (2003) Nucleotide-mediated calcium signaling in rat cortical astrocytes: role of P2X and P2Y receptors. Glia 43(3):218–203 [PubMed]
41. Bennett MR, Farnell L, Gibson WG (2005) A quantitative model of purinergic junctional transmission of calcium waves in astrocyte networks. Biophys J 89(4):2235–2250 [PubMed]
42. Bennett MR, Buljan V, Farnell L et al (2006) Purinergic junctional transmission and propagation of calcium waves in spinal cord astrocyte networks. Biophys J 91(9):3560–3571 [PubMed]
43. Parpura V, Basarsky TA, Liu F et al (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369(6483):744–747 [PubMed]
44. Schell MJ, Molliver ME, Snyder SH (1995) D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci USA 92(9):3948–3952 [PubMed]
45. Bezzi P, Volterra A (2001) A neuron-glia signalling network in the active brain. Curr Opin Neurobiol 11(3):387–394 [PubMed]
46. Araque A, Parpura V, Sanzgiri RP et al (1998) Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons. Eur J Neurosci 10(6):2129–2142 [PubMed]
47. Araque A, Sanzgiri RP, Parpura V et al (1998) Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J Neurosci 18(17):6822–6829 [PubMed]
48. Lee CJ, Mannaioni G, Yuan H et al (2007) Astrocytic control of synaptic NMDA receptors. J Physiol 581(Pt 3):1057–1081 [PubMed]
49. Fellin T, Pascual O, Gobbo S et al (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43(5):729–743 [PubMed]
50. Kang J, Jiang L, Goldman SA et al (1998) Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat Neurosci 1(8):683–692 [PubMed]
51. Newman EA, Zahs KR (1998) Modulation of neuronal activity by glial cells in the retina. J Neurosci 18:4022–4028 [PubMed]
52. Perea G, Araque A (2007) Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317(5841):1083–1086 [PubMed]
53. Pasti L, Volterra A, Pozzan T et al (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J Neurosci 17(20):7817–7830 [PubMed]
54. Araque A, Martin ED, Perea G et al (2002) Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices. J Neurosci 22:2443–2450 [PubMed]
55. Perea G, Araque A (2005) Synaptic regulation of the astrocyte calcium signal. J Neural Transm 112(1):127–135 [PubMed]
56. Perea G, Araque A (2006) Synaptic information processing by astrocytes. J Physiol Paris 99(2–3):92–97 [PubMed]
57. Fellin T, Sul JY, D’Ascenzo M et al (2006) Bidirectional astrocyte-neuron communication: the many roles of glutamate and ATP. Novartis Found Symp 276:208–217 [PubMed]
58. Rogawski MA, Loscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5:553–564 [PubMed]
59. Meldrum BS (1996) Update on the mechanism of action of antiepileptic drugs. Epilepsia 37:S4–S11 [PubMed]
60. Bezzi P, Carmignoto G, Pasti L et al (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281–285 [PubMed]
61. Fellin T, Pozzan T, Carmignoto G (2006) Purinergic receptors mediate two distinct glutamate release pathways in hippocampal astrocytes. J Biol Chem 281:4274–4284 [PubMed]
62. Bezzi P, Gundersen V, Galbete JL et al (2004) Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7:613–620 [PubMed]
63. Jourdain P, Bergersen LH, Bhaukaurally K et al (2007) Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci 10(3):331–339 [PubMed]
64. Tian GF, Azmi H, Takano T et al (2005) An astrocytic basis of epilepsy. Nat Med 11:973–981 [PMC free article] [PubMed]
65. Sarkisian MR (2001) Overview of the current animal models for human seizure and epileptic disorders. Epilepsy Behav 2(3):201–216 [PubMed]
66. Fellin T, Gomez-Gonzalo M, Gobbo S et al (2006) Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices. J Neurosci 26(36):9312–9322 [PubMed]
67. Fiacco TA, Agulhon C, Taves SR et al (2007) Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity. Neuron 54(4):611–626 [PubMed]
68. Tritsch NX, Bergles DE (2007) Defining the role of astrocytes in neuromodulation. Neuron 54(4):497–500 [PubMed]
69. Montana V, Malarkey EB, Verderio C et al (2006) Vesicular transmitter release from astrocytes. Glia 54:700–715 [PubMed]
70. Nakase T, Naus CC (2004) Gap junctions and neurological disorders of the central nervous system. Biochim Biophys Acta 1662(1–2):149–158 [PubMed]
71. Nemani VM, Binder DK (2005) Emerging role of gap junctions in epilepsy. Histol Histopathol 20(1):253–259 [PubMed]
72. Nilsen KE, Kelso AR, Cock HR (2006) Antiepileptic effect of gap-junction blockers in a rat model of refractory focal cortical epilepsy. Epilepsia 47(7):1169–1175 [PubMed]
73. Wallraff A, Köhling R, Heinemann U et al (2006) The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J Neurosci 26(20):5438–5447 [PubMed]
74. Suadicani SO, De Pina-Benabou MH, Urban-Maldonado M et al (2003) Acute downregulation of Cx43 alters P2Y receptor expression levels in mouse spinal cord astrocytes. Glia 42(2):160–171 [PMC free article] [PubMed]
75. Scemes E (2008) Modulation of astrocyte P2Y1 receptors by the carboxyl terminal domain of the gap junction protein Cx43. Glia 56(2):145–153 [PMC free article] [PubMed]
76. Kang J, Kang N, Lovatt D et al (2008) Connexin 43 hemichannels are permeable to ATP. J Neurosci 28(18):4702–4711 [PubMed]
77. Fields RD, Stevens B (2000) ATP: an extracellular signaling molecule between neurons and glia. Trends Neurosci 23:625–633 [PubMed]
78. Kandler K, Katz LC (1995) Neuronal coupling and uncoupling in the developing nervous system. Curr Opin Neurobiol 5:98–105 [PubMed]
79. Leite JP, Neder L, Arisi GM et al (2005) Plasticity, synaptic strength, and epilepsy: what can we learn from ultrastructural data? Epilepsia 46:134–141 [PubMed]
80. Franke H, Krügel U, Schmidt R et al (2001) P2 receptor-types involved in astrogliosis in vivo. Br J Pharmacol 134:1180–1189 [PubMed]
81. Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10(11):1369–1376 [PubMed]
82. Barros LF, Bittner CX, Loaiza A et al (2007) A quantitative overview of glucose dynamics in the gliovascular unit. Glia 55(12):1222–1237 [PubMed]
83. Cotrina ML, Nedergaard M (2005) Intracellular calcium control mechanisms in glia. In: Kettenmann H, Ransom BR (eds) Neuroglia, 2nd edn. Oxford University Press, New York, pp 229–239
84. Haas B, Schipke CG, Peters O et al (2006) Activity-dependent ATP-waves in the mouse neocortex are independent from astrocytic calcium waves. Cereb Cortex 16(2):237–246 [PubMed]
85. Atkinson L, Shigetomi E, Kato F et al (2003) Differential increases in P2X receptor levels in rat vagal efferent neurones following a vagal nerve section. Brain Res 977:112–118 [PubMed]
86. Newman EA (2003) Glial cell inhibition of neurons by release of ATP. J Neurosci 23:1659–1666 [PMC free article] [PubMed]
87. Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 362:299–309 [PubMed]
88. Fellin T, Pascual O, Haydon PG (2006) Astrocytes coordinate synaptic networks: balanced excitation and inhibition. Physiology (Bethesda) 21:208–215 [PubMed]
89. Pascual O, Casper KB, Kubera C et al (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116 [PubMed]
90. Roberts E (1984) GABA-related phenomena, models of nervous system function, and seizures. Ann Neurol 16:S77–S89 [PubMed]
91. Fabricius M, Fuhr S, Bhatia R et al (2006) Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain 129:778–790 [PubMed]
92. Strong AJ, Dardis R (2005) Depolarisation phenomena in traumatic and ischaemic brain injury. Adv Tech Stand Neurosurg 30:3–49 [PubMed]
93. Strong AJ, Fabricius M, Boutelle MG et al (2002) Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke 33:2738–2743 [PubMed]
94. Martins-Ferreira H, Nedergaard M, Nicholson C (2000) Perspectives on spreading depression. Brain Res Brain Res Rev 32:215–234 [PubMed]
95. Basarsky TA, Duffy SN, Andrew RD et al (1998) Imaging spreading depression and associated intracellular calcium waves in brain slices. J Neurosci 18:7189–7199 [PubMed]
96. Largo C, Ibarz JM, Herreras O (1997) Effects of the gliotoxin fluorocitrate on spreading depression and glial membrane potential in rat brain in situ. J Neurophysiol 78:295–307 [PubMed]
97. Largo C, Tombaugh GC, Aitken PG et al (1997) Heptanol but not fluoroacetate prevents the propagation of spreading depression in rat hippocampal slices. J Neurophysiol 77:9–16 [PubMed]
98. Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81:1065–1096 [PubMed]
99. Krügel U, Kittner H, Franke H et al (2001) Accelerated functional recovery after neuronal injury by P2 receptor blockade. Eur J Pharmacol 420(2–3):R3–R4 [PubMed]
100. Wang X, Arcuino G, Takano T et al (2004) P2X7 receptor inhibition improves recovery after spinal cord injury. Nat Med 10:821–827 [PubMed]

Articles from Purinergic Signalling are provided here courtesy of Springer