astrocyte dysfunction and epilepsy

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Binder D K and Steinhuser C Role of Astrocyte Dysfunction in Epilepsy. In: Philip A. Schwartzkroin, editor Encyclopedia of Basic Epilepsy Research, Vol 1.

Oxford: Academic Press; 2009. pp. 412-417.

4 may underlie deficient water and K homeostasis in the humanepileptogenic hippocampus. Proceedings of the National Academyof Sciences USA 102: 11931198.

E

general CNS depressants and must be taken chronically for in astrocytic channels and transporters described later

412 Glia/Astrocytes _ Role of Astrocyte Dysfunction in Epilepsy

Author's personal copyseizure suppression, they often have marked inhibitoryeffects on cognition.

Thus, more specific AEDs that target cellular andmolecular abnormalities responsible for epilepsy but notglobally affect cerebral function need to be developed. Inthis regard, recent developments in understanding glial(especially astrocytic) changes in epilepsy can potentiallyprovide novel therapeutic targets. For simplicity, in this

have been discovered in sclerotic hippocampi from tem-poral lobe epilepsy patients. However, the cellular andmolecular processes leading to astrocytic changes duringepileptogenesis are not yet understood.

Glial Glutamate Receptors and Transporters inTemporal Lobe Epilepsy

Role of Astrocyte Dysfunction in

D K Binder, University of California, Irvine, CA, USAC Steinhauser, University of Bonn, Bonn, Germany

2009 Elsevier Ltd. All rights reserved.

Introduction

Epilepsy comprises a group of brain disorders characterizedby the periodic and unpredictable occurrence of seizures.Even with optimal current antiepileptic drug (AED) ther-apy, 30% of patients have poor seizure control andbecome medically refractory. Because many AEDs act as

Further Reading

Beach TG, Woodhurst WB, MacDonald DB, and Jones MW (1995)Reactive microglia in hippocampal sclerosis associated with humantemporal lobe epilepsy. Neuroscience Letters 191: 2730.

de Lanerolle NC and Lee TS (2005) New facets of the neuropathologyand molecular profile of human temporal lobe epilepsy. Epilepsy andBehavior 7: 190203.

Eid T, Thomas MJ, Spencer DD, et al. (2004) Loss of glutaminesynthetase in the human epileptogenic hippocampus: A possiblemechanism for elevated extracellular glutamate in mesial temporallobe epilepsy. Lancet 363: 2837.

Eid T, Lee TS, Thomas MJ, et al. (2005) Loss of perivascular Aquaporin

article we refer to different types of cells with astroglialproperties as astrocytes.

Background and Results

Glial Morphological Changes in Temporal LobeEpilepsy

Alterations in astrocytic properties have been bestdescribed in the specific case of human temporal lobeepilepsy. The most common pathology found in patientswith medically-intractable temporal lobe epilepsy is hip-pocampal sclerosis, more generally termed mesial tempo-ral sclerosis. Mesial temporal sclerosis is characterized by

Encyclopedia of Basic Epilepsy Re

Eronica E, Boer K, van Vilet EA, et al. (2007) Complement activation inexperimental and human temporal lobe epilepsy. Neurobiology ofDisease 26: 497511.

Lee TS, Mane S, Eid T, et al. (2007) Gene expression in temporal lobeepilepsy is consistent with increased release of glutamate byastrocytes. Molecular Medicine 13: 113.

OConnor ER, Sontheimer H, Spencer DD, and de Lanerolle NC (1998)Astrocytes from human hippocampal epileptogenic foci exhibitaction potential like responses. Epilepsia 39: 347354.

Otis TS and Sofroniew MV (2008) Glia get excited. Nature Neuroscience11: 379380.

Steinhauser C, Haydon PG, and de Lanerolle NC (2008) Astrogialmechanisms of epilepsy. In: Engel J Jr. and Pedley TA (eds.)Epilepsy: A Comprehensive Textbook vol. 2, ch. 26. WoltersKluver/Lippincott, Williams & Wilkins.

pilepsy

neuronal cell loss in specific hippocampal areas, gliosis,microvascular proliferation, and synaptic reorganization.One striking hallmark of sclerotic hippocampus is thatwhile there is a specific pattern of neuronal loss, there isalso reactive gliosis with hypertrophic glial cells exhibit-ing prominent Glial Fibrillary Acidic Protein (GFAP)staining and long, thick processes. Most of the changesDysfunction of glutamate transport and synthesis

Glutamate transporters are expressed by several CNScell types, but astrocytes are primarily responsible forglutamate uptake. The astroglial transporter GLT-1 isresponsible for the clearance of bulk extracellular gluta-mate in the CNS, and increased extracellular levels ofglutamate have been found in epileptogenic foci. GLT-1knockout in mice caused spontaneous seizures and hip-pocampal pathology resembling alterations in temporallobe epilepsy patients with mesial temporal sclerosis.Several human studies have supported the hypothesisthat reduced or dysfunctional glial glutamate transportersin the hippocampus may trigger spontaneous seizures inpatients with mesial temporal sclerosis (Table 1), yet theunderlying mechanisms are unclear.

search (2009), vol. 1, pp. 412-417

ort

ee

e

GLAST #e

Glia/Astrocytes _ Role of Astrocyte Dysfunction in Epilepsy 413

Author's personal copyTemporal lobe epilepsy GLT-1 No chang

(Glutamine synthetase) (#)Temporal lobe epilepsy GluR1 (flip variant) "

Temporal lobe epilepsy mGluR2/3 "mGluR5 "mGluR8 "

Temporal lobe epilepsy Kir channel #Temporal lobe epilepsy Kir channel #

#Temporal lobe epilepsy Kir channel #Temporal lobe epilepsy AQP4 " overall

Table 1 Involvement of astroglial membrane channels, transp

Epilepsy syndrome Astroglial molecule Effect

Temporal lobe epilepsy GLT-1 No changGLAST No chang

Temporal lobe epilepsy GLT-1 #GLAST No chang

Temporal lobe epilepsy GLT-1 #

Alternatively, alterations in glutamate metabolism maybe important. de Lanerolles group has found reducedglutamine synthetase, an enzyme in astrocytes that convertsglutamate into glutamine, in sclerotic rather than in non-sclerotic hippocampus of temporal lobe epilepsy patients(Table 1). Downregulation of glutamine synthetase wouldslow down glutamateglutamine cycling and accumulationof the transmitter in astrocytes and in the extracellularspace. This condition would provide a metabolic mecha-nism for astrocyte-dependent hyperexcitability.

Alterations of ionotropic glutamate receptors

A few studies have addressed the potential involvementof ionotropic glutamate receptors in seizure generation.Astrocytes abundantly express receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA) subtype composed of the subunits GluR1 to

# perivasculaFocal cortical dysplasia mGluR2/3 "

mGluR5 "Tuberous sclerosis GLAST #

GLT-1 #Tuberous sclerosis Kir channel #Tumor-associated

epilepsy

GluR2 # Q/R editing

Tumor-associated

epilepsy

GLT-1 #GLAST Mislocalized

Tumor-associated

epilepsy

Kir channel #Mislocalized

Posttraumatic epilepsy Kir and Kv channels #

Posttraumatic epilepsy GLT-1 #GLAST No change

CTZ, cyclothiazide; EM, electron microscopy; IHC, immunohistoche

trodes; PC, patch clamp; PEPA, 4-[2-(phenylsulfonylamino)ethylthio]

reverse transcriptase polymerase chain reaction; WB, Western blotchanges in astroglial cells in epilepsy. Glia 54: 358368.

Encyclopedia of Basic Epilepsy R

ers, and receptors in specific epilepsy syndromes

Species Methods

Human IHC, WB, ISH

Human IHC

Human IHC, ISH

Human IHC, WB,

enzyme activity

Human PC, pharmacology(CTZ, PEPA), single-cell

rtPCR, RA

Human IHC

Human PC

Human ISM, Ba2

Rat (pilocarpine)

Human PC, Ba2, single-cell rtPCRHuman IHC, rtPCR, gene chip, EMGluR4. Combined functional and single-cell transcriptanalyses revealed that enhanced expression of GluR1flip variants accounts for the prolonged receptorresponses observed in hippocampal astrocytes of epilepsypatients with mesial temporal sclerosis (Table 1). Pro-longed opening of receptor will promote influx of Ca2

and Na ions. Steinhausers group has shown thatenhanced intracellular Na blocks inwardly rectifyingastroglial K (Kir) channels, further strengthening depo-larization and reducing the K buffering capacity ofastrocytes, and thus contributing to hyperexcitability.

Metabotropic glutamate receptors and

astroglial Ca2+ signalling in epilepsy

mGluR3 and mGluR5 are the predominant metabotropicglutamate receptor subtypes expressed by glial cells. Acti-vation of these receptors affects cAMP accumulation andleads to an increase in intracellular Ca2. Group II

rHuman IHC

Tsc1GFAPCKO mouse WB, PC

Tsc1GFAPCKO mouse PC, WB, Ba2, mRNA analysisHuman glioma rtPCR, sequencing

Human glioma IHC

Human glioma PC

WB, IHCRat (fluid-percussion

injury)

PC, ISM

Rat (ferrous chloride) WB

mistry; ISH, in situ hybridization; ISM, ion-sensitive microelec-

-2,6-difluoro-phenoxyacetamide; RA, restriction analysis; rtPCR,

. Modified from Binder DK and Steinha user C (2006) Functional

esearch (2009), vol. 1, pp. 412-417

mGluRs (mGluR 2, 3) have been shown to be coupled to

plasia (Table 1). However, the functional role of glial

cant morphological alterations that are absent in acute

taken up by glial cells. Any impairment of glial K uptake


Author's personal copymodels that have been studied.

Astrocyte Potassium and Water Channels

Since both extracellular K concentration and osmolarityhave been shown to markedly modulate neural excitabil-ity, it is plausible that changes in astrocytic K or waterchannels could contribute to hyperexcitability in epilepsy.Indeed, recent studies have found changes in astroglialKir channels and AQP4 water channels in temporal lobeepilepsy specimens.

K+ channels

During neuronal hyperactivity, extracellular [K] mayincrease from 3 mM to a ceiling of 1012 mM; and Kreleased by active neurons is thought to be primarily

mGluR upregulation in epilepsy is not yet clear.

Astrocytic Glutamate Releasein Epilepsy

Astrocytes are capable of releasing glutamate through aCa2-dependent process, which could be involved inseizure generation. In chemically-induced, acute epilepsymodels, it was recently reported that astrocytes contributeto the generation of synchronized epileptiform activity. Inthese studies, epileptiform discharges were provokedthrough the application of 4-aminopyridine, GABAAreceptor antagonists, or bath solutions containing lowconcentrations of divalent cations. It appeared that astro-cytic increase in [Ca2]i is sufficient to stimulate releaseof glutamate from glial cells, which was critical for thegeneration of paroxysmal depolarization shifts (PDSs), ahallmark of epileptiform activity. In addition, in vivoimaging showed that some antiepileptic drugs suppressedastrocytic Ca2-signalling. An important caveat to thesestudies is that human epilepsy is associated with signifi-

cAMP levels in cultured astrocytes. mGluR-triggered risein Ca2 may cause oscillations and initiate Ca2 wavepropagation within the astrocyte network, activate Ca2-dependent ion channels, and induce glutamate releasefrom astrocytes. In experimental epilepsy, reactive astro-cytes of the hippocampus persistently upregulatemGluR3, mGluR5, and mGluR8 protein. Electron micro-scopic and immunohistochemical inspection of hippo-campal tissue from temporal lobe epilepsy patientsrevealed expression of mGluR2/3, mGluR4, mGluR5,and mGluR8 in reactive astrocytes, suggesting an involve-ment of these receptors in gliosis. Upregulation of astro-glial mGluR2/3 and mGluR5 was also observed inepileptic specimens from patients with focal cortical dys-

Encyclopedia of Basic Epilepsy Rewould be expected to be proconvulsant. In the hippocam-pus, millimolar and even submillimolar increases in extra-cellular K concentration enhance epileptiform activity.High-K also reliably induces epileptiform activity inhippocampal slices from human patients with intractabletemporal lobe epilepsy and hippocampal sclerosis.

A primary mechanism for K reuptake is thought to bevia inwardly rectifying glial K channels (Kir channels).Glial Kir channels may contribute to K reuptake andspatial K buffering, which has been most clearly demon-strated in the retina. Although multiple subfamilies of Kirchannels exist (Kir1Kir7) differing in tissue distributionand functional properties, the expression of Kir4.1 inbrain astrocytes has been investigated most thoroughly.Pharmacological or genetic inactivation of Kir4.1 leads toimpairment of extracellular K regulation. However,members of the strongly rectifying Kir2 family may alsocontribute to astroglial K buffering.

Downregulation of astroglial Kir channels has beenfound in the injured or diseased CNS. Kir currents arereduced following injury-induced reactive gliosis in vitro,entorhinal cortex lesion, freeze lesion-induced corticaldysplasia, and traumatic and ischemic brain injury. Inaddition, several studies have indicated downregulationof Kir currents in specimens from patients with temporallobe epilepsy. Using ion-sensitive microelectrodes, U.Heinemanns group compared glial Ba2-sensitive K

uptake in the CA1 region of hippocampal slices obtainedfrom patients with or without mesial temporal sclerosis.Ba2, a blocker of Kir channels, augmented stimulus-evoked K elevation in non-sclerotic but not in scleroticspecimens, suggesting an impairment in K buffering insclerotic tissue. Direct evidence for downregulation of Kircurrents in the sclerotic CA1 region of hippocampus camefrom a comparative patch-clamp study in which a reduc-tion in astroglial Kir currents was observed in sclerotichippocampi compared with that in non-sclerotic hippo-campi (Table 1). These data indicate that dysfunction ofastroglial Kir channels could underlie impaired K buff-ering and contribute to hyperexcitability in epileptic tis-sue. When and how this dysfunction develops duringepileptogenesis is not yet clear.

Water channels

Alterations in astroglial water regulation could also highlyaffect excitability. Brain tissue excitability is extremelysensitive to osmolarity and the size of the extracellularspace (ECS). Decreasing ECS volume produces hyperex-citability and enhanced epileptiform activity; conversely,increasing ECS volume with hyperosmolar mediumattenuates epileptiform activity. These experimentaldata parallel extensive clinical experience indicating thathypo-osmolar states such as hyponatremia lower seizure

search (2009), vol. 1, pp. 412-417

threshold while hyperosmolar states elevate seizure Astrocyte Dysfunction Involved in other Epilepsy

potential role of astrocytes in the etiology of TS. These


Author's personal copythreshold.The aquaporins (AQPs) are a family of membrane pro-

teins that function as water channels inmanycell types andtissues in which fluid transport is crucial. Aquaporin-4(AQP4) is expressed ubiquitously by glial cells, especiallyat specialized membrane domains including astroglial end-feet in contact with blood vessels and astrocyte membranesthat ensheath glutamatergic synapses. Activity-inducedradial water fluxes in neocortex have been suggested tooccur as a result of water movement via aquaporin channelsin response to physiological activity. Mice deficient inAQP4 have shown marked decrease in accumulation ofbrain water (cerebral edema) following water intoxicationand focal cerebral ischemia and impaired clearance of brainwater inmodels of vasogenic edema, suggesting a functionalrole for AQP4 in brain water transport. Similarly, micedeficient in dystrophin or a-syntrophin, in which there ismislocalization of the AQP4 protein, also show attenuatedcerebral edema.

Alteration in the expression and subcellular localiza-tion of AQP4 has been described in sclerotic hippocampiobtained from patients with mesial temporal sclerosis.One study using immunohistochemistry, rt-PCR, andgene chip analysis reported an overall increase in AQP4expression in sclerotic hippocampi. However, using quan-titative immunogold electron microscopy, the same groupfound that there was mislocalization of AQP4 in thehuman epileptic hippocampus, with reduction in perivas-cular membrane expression (Table 1). The authorshypothesized that the loss of perivascular AQP4 perturbswater flux, impairs K buffering, and results in anincreased propensity for seizures.

Several lines of evidence support the hypothesis thatAQP4 and Kir4.1 may act in concert in K and H2Oregulation. First, reuptake of K into glial cells could beAQP4-dependent, as water influx coupled to K influx isthought to underlie activity-induced glial cell swelling.Second, studies in the retina have demonstrated subcellularco-localization of AQP4 andKir4.1 via both electronmicro-scopic and co-immunoprecipitation analyses. Third,Kir4.1/ mice, like AQP4/ mice, have impaired retinaland cochlear physiology presumably due to altered K

metabolism. Fourth, AQP4/ mice have remarkably slo-wed K reuptake in models of seizure and spreadingdepression in vivo associatedwith a near-threefold increasein seizure duration. Fifth, afferent stimulation of hippocam-pal slices from a-syntrophin-deficient mice demonstrates adeficit in extracellular K clearance. These data are consis-tent with the idea that AQP4 and Kir4.1 participate inclearance of K following neural activity. However, furtherstudies are required to clarify the expression and functionalinteraction of AQP4 and Kir4.1 in the brain and theirchanges during epileptogenesis.

Encyclopedia of Basic Epilepsy Rmice, which have conditional inactivation of the TSC1gene in GFAP-expressing cells (Tsc1GFAPCKO mice),develop severe spontaneous seizures by 2months of ageand die prematurely. Intriguingly, the time point of onsetof spontaneous seizures in these mice is concordant withincreased astroglial proliferation. Furthermore, two func-tions of astrocytes glutamate and K reuptake areimpaired in these mice. These mice display reducedexpression of the astrocyte glutamate transporters GLT1and GLAST. In addition, recent evidence indicates thatastrocytes from Tsc1GFAPCKO mice exhibit reduced Kirchannel activity, and hippocampal slices from thesemice demonstrated increased sensitivity to K-inducedepileptiform activity (Table 1). Together, these studiesdemonstrate that in this model, changes in glial propertiesmay be a direct cause of epileptogenesis.

Tumor-associated epilepsyTumor-associated epilepsy is an important clinical prob-lem, seen in approximately one-third of cases. Surgicalremoval of tumors usually results in seizure control,but many tumors cannot safely be resected, and tumor-associated seizures are often resistant to anticonvulsanttherapy. Classic epilepsy-associated brain tumors includeastrocytoma, oligodendroglioma, ganglioglioma, dysem-bryoplastic neuroepithelial tumor, and pleomorphic xan-thoastrocytoma. Microdialysis studies of gliomas haverevealed reduced glutamate in the tumor compared toperi-tumoral tissue. A glutamate hypothesis of tumor-associated epilepsy has been advanced which suggests thattumors excite surrounding tissue by glutamate overstimu-lation. Two lines of evidence are relevant to this hypothesis.First, the glutamate receptor subunitGluR2 has been foundto be underedited at the Q /R site in gliomas, which would

Syndromes

Tuberous sclerosis

Tuberous sclerosis (TS) is a multisystem genetic disorderresulting from autosomal dominant mutations of eitherTSC1 or TSC2 genes. The TSC1 gene encodes the proteinhamartin and TSC2 encodes tuberin, which are thoughtto be regulators of cell signalling and growth. Epilepsyoccurs in 8090% of cases of TS, frequently involvesmultiple seizure types and is often medically refractory.Cortical tubers represent the pathologic substrate of TS,and microscopically consist of a specific type of dysplasticlesion with astrocytosis and abnormal giant cells.Although this suggests that astrocytes are involved in thepathologic lesion, in itself this is not the evidence for acausative role of astrocytes in TS epileptogenesis. How-ever, recent evidence using astrocyte-specific TSC1 con-ditional knockout mice has provided insight into aesearch (2009), vol. 1, pp. 412-417

increase AMPA receptor Ca2 permeability and potential-

glutamate release at the margins of the tumor may initiateseizures in peritumoral neurons. A distinct potential mech-

in a posttraumatic epilepsy model induced by intracorti-cal ferrous chloride injection (Table 1), suggesting im-

sclerotic hippocampi from patients with temporal lobe


Author's personal copypaired glutamate transport. Further studies of the role ofglial cells in posttraumatic epilepsy appear warranted nowthat reliable posttraumatic epilepsy animal models havebeen developed.

Perspectives and Future Directions

Astrocytes undergo cellular and molecular changes inepilepsy, including alteration in glutamate transportersand receptors as well as Kir channels and water channels.So far, most of these changes have been demonstrated in

anism underlying tumor-associated epilepsy is altered K

homeostasis. In support of this hypothesis, both reduced Kircurrents and mislocalization of Kir4.1 channels have beenfound in malignant astrocytes (Table 1).

Posttraumatic epilepsy

Posttraumatic epilepsy refers to a recurrent seizure disor-der whose cause is believed to be traumatic brain injury. Itis a common and important form of epilepsy, and developsin a variable proportion of traumatic brain injury survi-vors depending on the severity of the injury and the timeafter injury. Anticonvulsant prophylaxis is ineffective atpreventing the occurrence of late seizures. Weight-dropand fluid-percussion injury animal models of posttrau-matic epilepsy have demonstrated characteristic struc-tural and functional changes in the hippocampus, suchas death of dentate hilar neurons and mossy fiber spr-outing. Recently, studies have also implicated alteredastrocyte function in posttraumatic epilepsy models.Recordings from glial cells in hippocampal slices 2 daysafter fluid-percussion injury demonstrated reduction intransient outward and inward K currents (Table 1), andantidromic stimulation of CA3 led to abnormal extracel-lular K accumulation in posttraumatic slices comparedto controls. This was accompanied by the appearance ofelectrical afterdischarges in CA3. Thus, this study sug-gests impaired K homeostasis in posttraumatic hippo-campal glia. Another study demonstrated reduction inexpression of the astrocyte glutamate transporter GLT1

ly result in increased glutamate release by glioma cells(Table 1). Second, glioma cells release larger than normalamounts of glutamate in vitro. The release of glutamatefrom glioma cells is accompanied by a marked deficit inNa-dependent glutamate uptake, reduced expression ofastrocytic glutamate transporters, and upregulation ofcystine-glutamate exchange (Table 1). Hence, glioma cell

Encyclopedia of Basic Epilepsy Reepilepsy or animal models resembling this particularhuman condition. However, the various functions of astro-cytes in modulation of synaptic transmission and gluta-mate, K and H2O regulation suggest that astrocytedysfunction could also be part of the pathophysiology ofother forms of epilepsy.

One important recent development is the recognitionof structural and functional heterogeneity of cellswith astroglial properties. It is clear that a subset ofhippocampal astroglial cells (classical astrocytes orGluT cells) expresses glutamate transporters and notionotropic glutamate receptors and another (NG2 gliaor GluR cells) expresses ionotropic glutamate receptorsbut not glutamate transporters. However, the lineagerelationship of NG2 glia/GluR cells and the relativeroles of bona fide astrocytes versus NG2 glia/GluR cellsin epilepsy still remain unclear. In addition, the functionalroles of ionotropic glutamate receptors, Kir and AQP4channels in these subsets of glial cells in the hippocampusare not yet understood. Hippocampal NG2 glia/GluRcells lack gap junctional coupling but receive directsynaptic input from GABAergic and glutamatergic neu-rons. Gap junctions may also regulate excitability,although available data are inconsistent regarding theimpact of altered connexin expression on epileptogen-esis. The availability of mice with genetically uncoupledastrocytes will allow examination of this question, byseparating the effects produced by alterations of neuro-nal versus glial gap junctions. It will be important infuture studies to examine the cellular and molecularproperties of subsets of hippocampal glial cells in humanepileptic tissue and unravel the course of their functionalalterations during epileptogenesis in appropriate animalmodels.

Another recent focus in astrocyte biology that maybecome important for epilepsy research is the gliovascu-lar junction. Microvascular proliferation in the sclerotichippocampus was noted as early as 1899, but the role ofthe vasculature and the blood-brain barrier in epilepsy isnot yet clear. The intimate relationship between astroglialendfeet ensheathing blood vessels, the targeted expressionof AQP4 and Kir4.1 on astroglial endfeet, and the role ofastrocytes in blood-brain barrier permeability and controlof microcirculation have only recently been appreciated.Local pathological alterations in the gliovascular junctioncould perturb blood flow, K and H2O regulation andconstitute an important mechanism in the generation ofhyperexcitability. Indeed, a recent study suggests thattransient opening of the blood-brain barrier is actuallysufficient for focal epileptogenesis. The cellular andmolecular roles of the gliovascular junction in metabolichomeostasis and changes during epileptogenesis are onlybeginning to be explored.

search (2009), vol. 1, pp. 412-417

In conclusion, the exact changes taking place in astro-glial functioning during epilepsy are still poorly under-stood. The term reactive gliosis is too descriptive andshould be replaced by careful morphological, biochemical,and electrophysiological studies of identified glial cellsubtypes in human tissue and animal models. In additionto changes in preexisting glial cell populations, newly-generated glial cells with distinct properties may migrate

Glutamate and GABA Transporters; Glial-Mediated Me-

chanisms of Epileptogenesis in Tuberous Sclerosis;

Further Reading

Binder DK and Steinhauser C (2006) Functional changes in astroglialcells in epilepsy. Glia 54: 358368.

During MJ and Spencer DD (1993) Extracellular hippocampal glutamateand spontaneous seizure in the conscious human brain. Lancet 341:16071610.

Eid T, Thomas MJ, Spencer DD, Runden-Pran E, Lai JC,Malthankar GV, Kim JH, Danbolt NC, Ottersen OP, and deLanerolle NC (2004) Loss of glutamine synthetase in the human


Author's personal copyPeritumoral Epilepsy; Properties of Glia in Epileptic

Brain; Tumor-Induced Epilepsy and Epileptogenic Poten-

tial of Brain Tumor Treatment; Neurotrophic Factors:

Role ofBDNF inAnimalModels of Epilepsy;Non-Synaptic

Mechanisms: Changes in Extracellular Ion Composition;

Changes in Extracellular Space as a Modulator of

Excitability and Epileptogenicity; Modulation of Neuronal

Excitability by Changes in Extracellular Ion Composition;

Role of Aquaporins in Non-Synaptic Mechanisms of

Epilepsy; Transporters: Function of Cell-Surface Gluta-

mate Transporters in the Brain: An Important Role for

Development and Preventing Seizures.

into the hippocampus and contribute to enhanced seizuresusceptibility. The available data likely represent onlythe tip of the iceberg in terms of the functional roleof astroglial cells in epilepsy. In view of the many physio-logic functions of astrocytes that have been elucidatedwithin the past decade, it can be expected that the nextfew years of research will yield evidence of similar impor-tant roles for glial cells in pathophysiology. Further study ofastrocyte alterations in epilepsy should lead to the identifi-cation of novel molecular targets that might open newavenues for the development of alternative antiepileptictherapies.

Acknowledgements

D.K.B. is supported by a American Epilepsy Society/Milken Family Foundation Early Career Physician Scien-tist Award. C.S. is supported by grants from the DeutscheForschungsgemeinschaft (SFB/TR3; SPP1172). We apol-ogize to all those whose work could not be discussedbecause of space constraints.

See also: Glia/Astrocytes: Astrocytic Regulation of

Neuronal Excitability; Glial Modulation of Excitability via

Encyclopedia of Basic Epilepsy Repileptogenic hippocampus: Possible mechanism for raisedextracellular glutamate in mesial temporal lobe epilepsy. Lancet363: 2837.

Hinterkeuser S, Schroder W, Hager G, Seifert G, Blumcke I, Elger CE,Schramm J, and Steinhauser C (2000) Astrocytes in thehippocampus of patients with temporal lobe epilepsy displaychanges in potassium conductances. The European Journal ofNeuroscience 12: 20872096.

Jansen LA, Uhlmann EJ, Crino PB, Gutmann DH, and Wong M (2005)Epileptogenesis and reduced inward rectifier potassium current intuberous sclerosis complex-1-deficient astrocytes. Epilepsia 46:18711880.

Kivi A, Lehmann TN, Kovacs R, Eilers A, Jauch R, Meencke HJ, vonDeimling A, Heinemann U, and Gabriel S (2000) Effects of barium onstimulus-induced rises of [K]o in human epileptic non-sclerotic andsclerotic hippocampal area CA1. The European Journal ofNeuroscience 12: 20392048.

Matthias K, Kirchhoff F, Seifert G, Huttmann K, Matyash M,Kettenmann H, and Steinhauser C (2003) Segregated expressionof AMPA-type glutamate receptors and glutamate transportersdefines distinct astrocyte populations in the mouse hippocampus.Journal of Neuroscience 23: 17501758.

Schwartzkroin PA, Baraban SC, and Hochman DW (1998) Osmolarity,ionic flux, and changes in brain excitability. Epilepsy Research 32:275285.

Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U,and Friedman A (2004) Lasting blood-brain barrier disruption inducesepileptic focus in the rat somatosensory cortex. Journal ofNeuroscience 24: 78297836.

Seifert G, Huttmann K, Schramm J, and Steinhauser C (2004)Enhanced relative expression of glutamate receptor 1 flip AMPAreceptor subunits in hippocampal astrocytes of epilepsy patientswith Ammons horn sclerosis. Journal of Neuroscience 24:19962003.

Steinhauser C and Seifert G (2002) Glial membrane channelsand receptors in epilepsy: Impact for generation andspread of seizure activity. European Journal of Pharmacology 447:227237.

Tian GF, Azmi H, Takano T, Xu Q, Peng W, Lin J, Oberheim N, Lou N,Wang X, Zielke HR, Kang J, and Nedergaard M (2005) An astrocyticbasis of epilepsy. Nature Medicine 11: 973981.

Volterra A and Steinhauser C (2004) Glial modulation of synaptictransmission in the hippocampus. Glia 47: 249257.

Wallraff A, Kohling R, Heinemann U, Theis M, Willecke K, andSteinhauser C (2006) The impact of astrocytic gap junctionalcoupling on potassium buffering in the hippocampus. Journal ofNeuroscience 26: 54385447.

Ye ZC, Rothstein JD, and Sontheimer H (1999) Compromisedglutamate transport in human glioma cells: Reduction-mislocalization of sodium-dependent glutamate transporters andenhanced activity of cystine-glutamate exchange. Journal ofNeuroscience 19: 1076710777.

esearch (2009), vol. 1, pp. 412-417

Role of Astrocyte Dysfunction in EpilepsyIntroductionBackground and ResultsGlial Morphological Changes in Temporal Lobe EpilepsyGlial Glutamate Receptors and Transporters in Temporal Lobe EpilepsyDysfunction of glutamate transport and synthesisAlterations of ionotropic glutamate receptorsMetabotropic glutamate receptors and astroglial Ca2+ signalling in epilepsy

Astrocytic Glutamate Release in EpilepsyAstrocyte Potassium and Water ChannelsK+ channelsWater channels

Astrocyte Dysfunction Involved in other Epilepsy SyndromesTuberous sclerosisTumor-associated epilepsyPosttraumatic epilepsy

Perspectives and Future DirectionsAcknowledgementsSee alsoFurther Reading

astrocyte dysfunction and epilepsy

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