The presence of ionotropic and metabotropic neurotransmitter receptors led to the conclusion that astrocytes are endowed with the machinery to sense and respond to neuronal activity. Recent studies have implicated astrocytes in important physiological roles in the CNS, such as synchronisation of neuronal firing, ion homeostasis, neurotransmitter uptake, glucose metabolism and regulation of the vascular tone 1. Astrocytes are abundantly coupled through gap junctions allowing them to redistribute elevated K+ from sites of excessive neuronal activity to sites of lower extracellular K+ concentration. Evidence is now emerging indicating that dysfunctional astrocytes are crucial players in epilepsy. Investigation of specimens from patients with pharmacoresistant temporal lobe epilepsy and epilepsy models revealed alterations in expression, localization and function of astroglial K+ and water channels, entailing impaired K+ buffering. Moreover, malfunction of glutamate transporters and the astrocytic glutamate-converting enzyme, glutamine synthetase, as observed in epileptic tissue suggested that astrocyte dysfunction is causative of hyperexcitation, neurotoxicity and the generation or spread of seizure activity. Accordingly, dysfunctional astrocytes should be considered as promising targets for new therapeutic strategies. In this chapter, we will summarize current knowledge of astrocyte dysfunction in temporal lobe epilepsy and discuss putative mechanisms underlying these alterations.
Recent work has identified glial cells and astrocytes in particular, as active partners in neural information processing. Application of advanced electrophysiological and Ca2+ imaging techniques unravelled that astrocytes in acute brain slices or after fresh isolation from the tissue express a similar broad spectrum of functional ion channels and transmitter receptors as neurons 2. The presence of ionotropic and metabotropic neurotransmitter receptors led to the conclusion that astrocytes are endowed with the machinery to sense and respond to neuronal activity. In 1994 two groups discovered that elevation of the intracellular Ca2+ concentration [Ca2+]i in cultured astrocytes upon membrane receptor activation can induce glial release of glutamate 3,4. This astonishing finding for the first time demonstrated that astrocytes are sensing neuronal activity and feed back to neurons to modulate CNS signalling 5. Later studies corroborated the view that astrocytes are direct communication partners of neurons and dynamically interact with synapses through uptake of neurotransmitters, receptor-mediated Ca2+ signalling and subsequent gliotransmitter release. The intimate morphological and physiological interconnection between both cell types gave rise to the term tripartite synapse which comprises not only pre- and postsynaptic elements but also the astrocytic process 6,7.
According to a long-standing concept, astrocytes supply neurons with nutrition metabolites and oxygen. Fundamental new insight into this aspect of astrocyte function was gained through the discovery that astrocytes control in an activity-dependent manner cerebral blood flow, by releasing vasoactive substances such as polyunsaturated fatty acids, adenosine and prostaglandins 8,9,10. In addition to the only recently discovered modulatory actions on brain signalling and circulation, astrocytes are known for decades to serve homeostatic functions, including the clearance of neuronally released K+ and glutamate from the extracellular space. Astrocytes are abundantly coupled through gap junctions allowing them to redistribute elevated K+ from sites of excessive neuronal activity to sites of lower extracellular K+ concentration.
Despite the fact that the pathways enabling activation of these cells under physiological conditions are still ill-determined, evidence is emerging suggesting a critical role of astrocyte dysfunction in the pathogenesis of neurological disorders, including epilepsy 11. Investigation of specimens from patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and corresponding animal models of epilepsy revealed alterations in expression, subcellular localization and function of astroglial K+ and water channels, resulting in impaired K+ buffering. Moreover, malfunction of glutamate transporters and the astrocytic glutamate-converting enzyme, glutamine synthetase (GS), as observed in epileptic tissue suggested that astrocyte dysfunction is causative of hyperexcitation, neurotoxicity and the generation or spread of seizure activity. Accordingly, dysfunctional astrocytes should be considered as promising targets for new therapeutic strategies. In this chapter we will summarize current knowledge of astrocyte dysfunction in MTLE and discuss putative mechanisms underlying these alterations.
IMPAIRED K+ BUFFERING IN TEMPORAL LOBE EPILEPSY
Loss of inwardly rectifying K+ channels in MTLE
Neuronal activity, propagation of action potentials and synaptic activity after local depolarization, lead to fast fluctuations of the extracellular K+ concentration [K+]o because of the restricted extracellular space volume 12. If increases of [K+]o would remain uncorrected, the resting potential would become more positive and affect activation of transmembrane ion channels, receptors und transporters. During neuronal hyperactivity in vivo, [K+]o, may increase from 3 mM to a ceiling level of 10–12 mM 13. Such high [K+]o levels can generate epileptiform activity in acute brain slices. Two different mechanisms are thought to balance [K+]o during neuronal activity: K+ uptake and spatial K+ buffering (for review see 14). K+ uptake, mediated by Na, K-ATPase or Na-K-Cl cotransporters, is accompanied by cell swelling and local depolarization of astrocytes. Spatial K+ buffering instead is driven by the glial syncytium membrane potential and the local K+ equilibrium potential. This allows transfer of K+ from regions of elevated [K+]o, through the syncytium, to regions of lower [K+]o. Spatial buffering depends on proper distribution and function of astrocytic K+ channels, water channels and gap junctions. In astrocytes, the inward rectifying K+ channel Kir4.1, which is activated by intracellular ATP, is thought to allow for K+ influx at negative membrane potentials (for review see 15,16).
Because of its presumed role in K+ homeostasis, properties of astroglial Kir channels have been investigated in experimental and human epilepsy. Measurements of [K+]o with ion sensitive microelectrodes and patch-clamp studies suggested that impaired K+ buffering in sclerotic human hippocampus resulted from altered Kir channel expression. Differences were observed in the effect of Ba2+ on stimulus-induced changes in [K+]o in the CA1 region of hippocampal brain slices obtained from MTLE patients with hippocampal sclerosis (MTLE-HS) or without sclerosis (non-HS). In non-HS tissue, Ba2+ application significantly enhanced [K+]o while this effect was not observed in HS specimens. Since Ba2+ is a blocker of Kir channels in astrocytes of the hippocampus 17, this findings suggested impaired function of these channels in the sclerotic tissue 18,19. The hypothesis could be confirmed with patch clamp analyses demonstrating down-regulation of Kir currents in the sclerotic human CA1 region of MTLE patients 20,21. Accordingly in MTLE-HS, impaired K+ buffering and enhanced seizure susceptibility result from reduced expression of Kir channels. However, it is still unclear whether these changes are cause or consequence of the condition.
Fine mapping of a locus on mouse chromosome 1 identified KCNJ10, the gene encoding Kir4.1, as a candidate gene exhibiting a potentially important polymorphism with regard to fundamental aspects of seizure susceptibility 22. Similarly, variations in KCNJ10 in the human genome associate with multiple seizure phenotypes. Missense mutations of KCNJ10 influence the risk of acquiring forms of human epilepsy 23. Mutations in the KCNJ10 gene encoding Kir4.1 channels cause a multiorgan disorder in patients with clinical features of epilepsy, sensorineural deafness, ataxia and electrolyte imbalance 24,25. These patients suffer from generalized tonic-clonic seizures and focal seizures since childhood. Single nucleotide mutations in the KCNJ10 gene cause missense or nonsense mutations on the protein level in the pore region, transmembrane helices or the C-terminus, the latter resulting in deletion of a PDZ binding domain and improper membrane localization of Kir4.1. These loss-of-function mutations of KCNJ10 are homozygous or compound heterozygous. Experiments with heterologous expression systems demonstrated that the mutations indeed affect channel function and lead to reduced transmembrane currents 24.
Genetic downregulation of Kir4.1, the main Kir channel subunit in astrocytes 17,26,27,28, profoundly reduced the ability of astrocytes to remove glutamate and K+ from the extracellular space, both in cell culture 29 and in vivo
30. General knockout of Kir4.1 leads to early postnatal lethality and mice with astrocytic deletion of the channel developed a pronounced behavioral phenotype, including seizures 30,31. Thus, dysfunction of Kir4.1 is observed in different forms of epilepsy ().
Epilepsy-associated alterations of functional properties in astrocytes. (1) Seizure activity leads to an increase in extracellular K+ concentration. Downregulation of Kir channels was observed in astrocytes in human and experimental epilepsy. (2) Gap (more...)
Interestingly, spinal cord injury-induced downregulation of Kir4.1 in the spinal cord can be partially rescued by administration of β-estradiol. Inhibition of oestrogen receptors also reduces Kir4.1-mediated currents, suggesting that Kir4.1 channel expression depends on nuclear oestrogen receptor signalling under physiological conditions 32.
Gap junctions and K+ buffering
A prerequisite for the operation of spatial K+ buffering is the presence of Kir channels and connexins forming gap junctions 33,14. According to this concept, K+ entry into the astrocytic network occurs at sites of maximal extracellular K+ accumulation, driven by the difference between glial syncytium membrane potential and the local K+ equilibrium potential. Since K+ propagates through the glial network, at sites distant to elevated [K+]o a driving force for K+ efflux results because here local depolarization exceeds the K+ equilibrium potential. Surprisingly, clearance and redistribution of K+ were still preserved in the hippocampal stratum radiatum (but not in the lacunosum-moleculare) of mice with coupling deficient astrocytes, indicating that gap junction-independent mechanisms add to K+ homeostasis in the brain (e.g. indirect coupling 34; ). Nevertheless, genetic deletion of astrocyte gap junctions leads to impaired K+ buffering, spontaneous epileptiform activity and a decreased threshold for eliciting seizure activity 34.
Impaired spatial buffering in the stratum lacunosum moleculare of mice with genetic deletion of Cx43 and Cx30 in astrocytes (dko mice). (A) Experimental setup for the analysis of laminar profiles of changes in [K+]o. Stimulation was performed in the alveus (more...)
Interplay between Kir channels and AQP4 in K+ buffering
Ultrastructural analyses in rat demonstrated spatial overlap of Kir4.1 and the water channel aquaporin 4 (AQP4) in astroglial endfeet contacting the capillaries 35,36. This finding gave rise to the hypothesis that K+ clearance through Kir channels might critically depend on concomitant transmembrane flux of water in a given cell, to dissipate osmotic imbalances due to K+ redistribution. Subsequent functional work corroborated this idea, by showing that in mice the clearance of extracellular K+ is compromised if the number of perivascular AQP4 channels is decreased 37. Similarly, impaired K+ buffering and prolonged seizure duration was observed in AQP4 knockout mice 38. However, later work provided evidence against the concept of functional coupling of AQP4 and Kir4.1 channels 39,40. Thus, there is a need to identify alternate mechanism(s) underlying hyperactivity associated with AQP4 deficiency. Epileptic rats show mislocalization of AQP4 in astrocytic endfeet contacting blood vessels in the hippocampus. Eight weeks after status epilepticus, immunohistochemistry revealed loss of AQP4 in vacuolized astrocytes of the hippocampus. Instead, AQP1 was found in astrocytes, a protein not expressed by these cells under physiological conditions. Non-vacuolized astrocytes still contained AQP4, even at higher levels, and in addition expressed AQP941. In MTLE-HS patients, immunostaining indicated loss of AQP4 in vasculature-associated astrocyte endfeet as compared with specimens from non-HS patients 42. The decrease of perivascular AQP4 channels might be secondary, following disruption of the dystrophin complex that is essential for anchoring of AQP4 in the plasma membrane 43. Together, these findings suggest that in MTLE-HS, dislocation of water channels in concert with decreased expression of Kir channels in astrocytes might underlie impaired K+ buffering and increased seizure propensity (). The functional consequence of the upregulation of AQP subunits other than AQP4 in astrocytes of epileptic tissue remains unclear yet. Characterization of DNA variations in MTLE-HS patients with antecedent febrile seizures (MTLE-FS) identified single nucleotide polymorphisms (SNPs) in the KCNJ10 gene, the region between KCNJ9 and KCNJ10 and in the AQP4 gene. The combination of KCNJ10 and AQP4 gene variations was associated with MTLE-FS, supporting the hypothesis that impaired K+ and water homeostasis is involved in the etiopathogenesis of MTLE 44.
In addition to spatial buffering, transient K+ accumulation can be counterbalanced by net K+ uptake through Na, K-ATPase and the Na-K-Cl co-transporter NKCC1, at the cost of cell swelling due to concomitant water influx (reviewed by 14). In rodent hippocampus, the Na, K-ATPase was reported to have a potential role in maintaining low [K+]o levels and to clear elevations in [K+]o after epileptiform activity 45,46. However, whether alterations in net K+ uptake contribute to the enhanced [K+]o levels seen in epileptic tissue has still to be elucidated.
AMBIGUOUS ROLE OF GAP JUNCTIONS IN EPILEPTOGENESIS
The abundant expression of gap junctions in astrocytes and their formation as a functional syncytium enables long range intercellular exchange of ions, nutritional metabolites, amino acids and nucleotides. The permeability of gap junctions is regulated by endogenous membrane receptors, second messengers and pH (see review by 47). Thus, trafficking of nutritional metabolites such as glucose-6-phosphate and lactate through astrocytes is controlled by endogeneous compounds that are released by endothelial cells, astrocytes and neurons in an activity dependent manner 48. In addition to the aforementioned homeostatic functions, astrocytic gap junctions may affect neuronal migration and proliferation 49,50,51. Recent work revealed that inhibition of gap junction coupling not only enhances glucose uptake, synthesis of nucleic acids and proliferation of astrocytes 52. Gap junctions formed by Cx43 and Cx30 also allow intercellular trafficking of glucose through the astrocytic network and deliver energetic metabolites from blood vessels to neurons, to maintain synaptic transmission in the murine brain 53 (). Glucose uptake and trafficking was dependent on synaptic transmission: It was increased during epileptiform activity and, in turn, glucose delivery through the astrocytic network was needed to sustain epileptiform activity. Neuronal activity was sustained by the transport of nutrition metabolites through astrocytic network even under conditions of transient limited substrate availability (see also 51).
Cx43 and Cx30 comprise the main connexins forming gap junctions in astrocytes of the CNS 54 and as discussed above, its cell type-specific deletion in mice led to the generation of spontaneous epileptiform activity and a decreased threshold for evoking seizure activity 34. Disruption of the blood-brain-barrier and albumin-dependent generation of epilepsy in rat is accompanied by a transient decrease of both connexin transcripts 55,56. These findings are in line with the long-standing concept that astrocyte gap junctions are essential for proper K+ regulation 57 and help counteracting the generation of epileptiform activity. However, an opposite effect was observed in organotypic hippocampal slice cultures where long-term block of gap junctions through Cx43 mimetic peptides attenuated spontaneous seizure like events (but not evoked epileptiform responses 58). The authors also observed that serum deprivation strongly reduced spontaneous recurrent network activity and assigned this effect to a neuroprotective role of gap junctional communication. Hence, a decrease of gap junction permeability seems to exert opposite effects on excitability: A fast onset, pro-convulsive effect due to impaired K+ redistribution, but a delayed anti-epileptic effect because of disruption of neuronal energy supply.
Despite these intriguing new insights into astrocyte function, the role of gap junctions in human epilepsy is still unresolved. Published data are not always consistent, reflecting that i) human epilepsy can not be considered a uniform condition, ii) most of the currently available gap junction blockers do not distinguish between neuronal and glial gap junctions and iii) these blockers usually have dramatic side effects 59. Moreover, analysis of tissue samples is restricted to the chronic phase of the disorder and is likely to be affected by patients’ long-lasting treatment with different AEDs, a problem inherent to experiments with neurosurgically resected specimens. Increased expression of Cx43 protein was observed in low-grade tumors and reactive astrocytes of human epileptic cortical tissue surrounding tumors although high-grade gliomas exhibited great variations in Cx4360. Specimens from pharmacoresistant MTLE-HS patients showed strongly enhanced Cx43 immunoreactivity and transcript levels 61,62,63. The authors speculate that upregulation of connexins might represent a compensatory response of astrocytes to cope with the enhanced K+ release during seizure activity. However, in the light of the aforementioned findings, enhanced coupling could also serve to fuel hyperactivity and thereby exacerbate generalized seizures. Importantly, it has to be emphasized that any functional evidence of enhanced gap junction coupling in human epilepsy is yet missing, which considerably limits conclusions that can be drawn from the above studies.
GLUTAMATE UPTAKE IN EPILEPSY
Glutamate transporter in astrocytes
The uptake of glutamate that helps to terminate the action of this neurotransmitter at CNS synapses is mainly mediated by transporters localized at the astrocytic membrane. The high efficiency of these glial transporters assures maintain low concentrations of extracellular glutamate to prevent excitotoxic cell death 64,65. They are densely packed and keep the extracellular glutamate concentration in the nM range, preventing significant receptor activation 66,67,68. Fine tuning of extrasynaptic glutamate through glial glutamate transporters is important for proper synaptic function and plasticity 69,70,71,72. Downregulation of glial glutamate transporters or metabolic inhibition of the glutamate-to-glutamine converting enzyme, GS, immediately caused extracellular accumulation of the transmitter which, if reaching μM concentrations, caused depolarization, compromised synaptic transmission and induced neuronal death 73,74,75,66. It is therefore not surprising that dysfunction of the astrocytic glutamate transporters, EAAT1 and EAAT2, is observed under various pathological conditions, including epilepsy 11 ().
Excess of extracellular glutamate is found in human epileptogenic tissue and can induce recurrent seizures and neuronal cell death 76,77. This may occur through the activation of neuronal and glial glutamate receptors. Indeed, a large body of evidence has shown that the activation of astrocytes by neuronal activity-derived glutamate is mainly due to activation of metabotropic glutamate receptors (mGluRs) mGluR3 and mGluR5. Activation of these receptors affects cAMP accumulation and leads to increases in intracellular Ca2+, respectively. The Ca2+ rise may oscillate and initiate Ca2+ wave propagation within the astrocyte network, activate Ca2+-dependent ion channels and induce glutamate release from astrocytes (cf. Sodium Channel Mutations and Epilepsy). In epilepsy models, elevated protein levels for mGluR3, mGluR5 and mGluR8 have been found 59 (). High-resolution analysis of hippocampal specimens from TLE patients detected mGluR2/3, mGluR4 and mGluR8 in reactive astrocytes, suggesting an involvement of these mGluRs in gliosis 78. Enhanced levels of astroglial mGluR2/3 and mGluR5 were also observed in epileptic specimens from patients with focal cortical dysplasia 79. Since their activation affects expression of EAAT1 and EAAT280 and elevates [Ca2+]i, astrocytic mGluRs might contribute to the generation of seizure foci.
Different reports exist about the regulation of glial glutamate transporters in patients presenting with pharmacoresistant MTLE. Employing in situ hybridization and Western blot in specimens from patients with HS, 81 did not find changes of EAAT1 or EAAT2. In contrast, other groups reported downregulation of EAAT2 immunoreactivity in the CA1 region displaying profound neuronal loss in human HS 82,83. EAAT1 was found increased in the sclerotic CA2/3 region 83. Later work showed downregulation of EAAT1 and EAAT2 in the CA1 region in HS and emphasized that currently it is still unclear whether this reduction is causative of the condition or rather represents a consequence 84. A critical analysis of immunohistochemical, Western blot and mRNA data hinted at redistribution, rather than a reduction, of glial glutamate transporter in human epilepsy, which was considered inadequate to account for the high glutamate concentrations during seizures 85. The authors concluded that under these conditions, glutamate uptake is influenced by factors other than transporter protein levels, e.g. changes in the cells’ metabolic state and downregulation of GS (see next section).
Recent work reported that expression of EAAT2 is critically dependent on synaptic activity. In this study, EAAT2-mediated uptake was decreased after nerve fiber transection or neurodegeneration in a mouse model of amyotrophic lateral sclerosis (ALS) 86. Beta-lactam antibiotics increased glutamate uptake in primary human astrocytes through NFκB mediated EAAT2 promoter activation 87. Hence, the antibiotics might represent a therapeutical tool to counteract glutamate transporter dysfunction in neurological disorders such as ALS and epilepsy 88.
Depolarization of astrocytes by inadequate K+ buffering led to compromised functioning of the glial transporters 29,30. In a rat model of cortical dysplasia, pharmacological inhibition of glial glutamate transporters in the lesion area led to opening of neuronal NMDA receptors, prolonged synaptic currents and decreased the threshold for the induction of epileptiform activity 89. This enhanced activity of NMDA receptors also triggered dephosphorylation of Kv2.1 K+ channels, produced a negative shift of its voltage-dependent activation, and hence modulated excitability and neuronal plasticity in mice 90.
Conversion of glutamate to glutamine by astrocytes
For effective removal of excess extracellular glutamate, the transmitter must be converted by GS into the receptor-inactive substrate glutamine, under consumption of ATP and ammonia. Increasing evidence indicates a loss of this astrocyte-specific enzyme in epilepsy. In MTLE-HS patients, loss of GS in the hippocampus was accompanied by elevated extracellular glutamate levels 91,92,93. Infusion of 13C-labeled glucose before resection of the hippocampus from MTLE-HS patients revealed increased glutamate concentration, slowed glutamate-to-glutamine cycling and decreased glutamine concentrations. Thus, failure of glutamate detoxification could account for continuing excitotoxicity and contribute to the pathogenesis 94
In experimental epilepsy, upregulation of GS and GFAP was observed in the latent phase, prior to recurrent seizure onset while in the chronic phase GS was downregulated with elevated GFAP immunoreactivity persisting 95. By contrast, glutamate dehydrogenase, another glutamate degrading enzyme, remained unaltered in this rat model. Compatible with a potential causative role of GS loss in initiating epilepsy was the finding that pharmacological inhibition of GS produced recurrent seizure activity and rat brain pathology resembling MTLE-HS 96. In the pentylenetetrazol epilepsy model, immunohistochemistry revealed unchanged GS protein levels. However, the enzyme underwent stress-induced nitration and partial inhibition in severely affected hippocampal regions which might result in locally altered glutamate and GABA metabolism 97. Genetic inactivation of GS in mice leads to early embryonic lethality while GS deletion on one allele increases the susceptibility to febrile seizures 98.
Inhibition of GS in astrocytes and/or glutamine transporters in neurons reduced amplitudes of evoked IPSCs and GABA release from interneurons in the hippocampus (). Hence, in rat the glial glutamate-glutamine cycle is a major contributor to synaptic GABA release and regulates inhibitory synaptic strength 99, while inhibition of GS did not significantly affect glutamatergic transmission in the same species 100. However, for periods of intense neuronal activity or epileptiform activity, glial supply of glutamine and the transport into neurons is required 101.
MTLE-HS is characterized by neuronal loss and reactive astrogliosis. In a model of selective astrogliosis, which leaves properties of neurons and microglia unaltered, deficient neuronal inhibition was observed in the hippocampus while excitatory neurotransmission remained unchanged. Decreased inhibition resulted from impaired GS activity, compromised glutamine availability and reduced GABA release from interneurons 102. These astrogliosis-associated deficits generated hyperactivity, emphasising the impact of proper GS function for inhibitory neurotransmission and prevention of seizures generation.
CONCLUDING REMARKS
The novel view that considers astrocytes as communication partners of neurons rather than ‘brain glue’ has rekindled the question regarding the role of these cells in neurological disorders such as epilepsy. Indeed, an increasing body of evidence has documented astroglial dysfunction, and even dysregulation of astroglia-specific functions in human and experimental epilepsy. This particularly concerns impaired uptake/conversion of glutamate and removal/redistribution of K+ as observed in MTLE-HS. A number of key questions needs, however, to be addressed before a unifying picture can be proposed. For example it is still unclear whether the reported glial alterations are causative or a consequence of the condition. In addition, difficulties arise from the fact that the term “astrocyte” covers a heterogeneous group of cells, and this complicates comparison of individual studies. It is worth, however, underlining that the molecular, functional and structural characterization of astroglial heterogeneity is a rapidly evolving field that may soon lead to a better definition of astroglial subtypes. In a comprehensive approach that uses modern molecular genetics and in vivo models we may have now the opportunity to clarify the specific roles of astroglia in epilepsy and to develop novel therapeutic approaches to fight this disorder.
ACKNOWLEDGEMENTS
Work of the authors is supported by Deutsche Forschungsgemeinschaft (grants SPP 1172 SE 774/3, SFB/TR3 C1, C9) and European Commission (FP7-202167 NeuroGLIA). We thank Dr. I. Nauroth for comments on the manuscript, and apologize to all those whose work could not be discussed due to space constraints.
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