Astrocyte Dysfunction and Epilepsy

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This article was originally published in the Encyclopedia of Basic Epilepsy Research, published by Elsevier, and the attached copy is provided by Elsevier Research, for the author's benefit and for the benefit of the author's institution, for noncommercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who you know, and providing a copy to your institution’s administrator.

All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial Binder D K and Steinhäuser Steinhäuser C Role of Astrocyte Dysfunction Dysfunction in Epilepsy. In: Philip A. Schwartzkroin, editor Encyclopedia of Basic Epilepsy Research,  Research, Vol 1. Oxford: Academic Press; 2009. pp. 412-417.

 

412   Glia/Astrocytes  _  Role of Astrocyte Dysfunction in Epilepsy

 

Further Reading Beach TG, Woodhurst WB, MacDonald DB, and Jones MW (1995) Reactive microglia in hippocampal sclerosis associated with human temporal lobe epilepsy. Neuroscience epilepsy.  Neuroscience Letters 191: Letters  191: 27–30. de Lanerolle NC and Lee TS (2005) New facets of the neuropathology and molecular profile of human temporal lobe epilepsy. epilepsy. Epilepsy  Epilepsy and  Behavior   7: 7: 190–203. Eid T, Thomas MJ, Spencer DD,  et al. (2004) al.  (2004) Loss of glutamine synthetase in the human epileptogenic hippocampus: A possible mechanism for elevated extracellular glutamate in mesial temporal lobe epilepsy. Lancet  epilepsy.  Lancet  363:  363: 28–37. Eid T, Lee TS, Thomas MJ, et MJ,  et al. (2005) al.  (2005) Loss of perivascular Aquaporin 4 may underlie deficient water and K þ homeostasis in the human epileptogenic hippocampus. Proceedings hippocampus.  Proceedings of the National Academy  of Sciences USA  USA   102: 1193–1198.

Eronica E, Boer K, van Vilet EA,  et al. (2007) al.  (2007) Complement activation in experimental and human temporal lobe epilepsy. Neurobiology epilepsy.  Neurobiology of  Disease 26: Disease  26: 497–511. Lee TS, Mane S, Eid T, et T,  et al. (2007) al.  (2007) Gene expression in temporal lobe epilepsy is consistent with increased release of glutamate by astrocytes. Molecular astrocytes.  Molecular Medicine 13: Medicine  13: 1–13. O’Connor ER, Sontheimer H, Spencer DD, and de Lanerolle NC (1998)  Astrocytes from human hippocampal epileptogenic foci exhibit action potential like responses. Epilepsia responses.  Epilepsia 39:  39: 347–354. Otis TS and Sofron Sofroniew iew MV (2008) Glia get exc excited. ited. Nature  Nature Neuroscience 11: 379–380. Steinhauser C, Haydon PG, and de Lanerolle NC (2008) Astrogial mechanisms of epilepsy. In: Engel J Jr. and Pedley TA (eds.) Epilepsy: A Comprehensive Textbook  vol.  vol. 2, ch. 26. Wolters Kluver/Lippincott, Williams & Wilkins.

Role of Astrocyte Dysfunction in Epilepsy University of Calif California ornia,, Irvin Irvine, e, CA, USA  D K Binder,   University   ¨ user, ¨ user,   University of Bonn, Bonn, Germany C Steinha ã   2009

Else Elsevie vierr Ltd Ltd.. All rig rights hts reserv reserved. ed.

Introduction Epilepsy Epileps y compris comprises es a group group of brain brain diso disorder rderss cha charact racteriz erized ed by the periodic and unpredictable occurrence of seizures. Even with optimal current antiepileptic drug (AED) therapy,   30% of patien patients ts have have poor poor seizu seizure re contr control ol and become medically refractory. Because many AEDs act as general CNS depressants and must be taken chronically for seizure seiz ure suppress suppression, ion, the they y oft often en have have mark marked ed inhi inhibito bitory ry effects on cognition. Thus hus,, more more specifi specificc AEDs AEDs that target cellular cellular and molecular abnormalities responsible for epilepsy but not globally affect cerebral function need to be developed. In this regard, recent developments in understanding glial (especially astrocytic) changes in epilepsy can potentially provide novel therapeutic targets. For simplicity, in this article we refer to different types of cells with astroglial properties as ‘astrocytes.’

neuronal cell loss in specific hippocampal areas, gliosis, microvascular proliferation, and synaptic reorganization. One striking hallmark of sclerotic hippocampus is that while there is a specific pattern of neuronal loss, there is also ‘reactive gliosis’ with hypertrophic glial cells exhibiting prominent Glial Fibrilla Fibrillary ry Acidic Protein (GF (GFAP) AP) staining and long, thick processes. Most of the changes in astrocytic astrocytic channels and transporters transporters described later have been discovered in sclerotic hippocampi from temporal lobe epilepsy patients. However, the cellular and molecular processes leading to astrocytic changes during epileptogenesis are not yet understood. Glial Glutamate Receptors and Transporters Transporters in Temporal Lobe Epilepsy  Epilepsy   Dysfunction of glutamate transport and synthesis

Al Alte tera ratio tions ns in as astro trocy cyti ticc prop proper ertie tiess have have be been en be best st described in the specific case of human temporal lobe epilepsy. The most common pathology found in patients with medically-intractable temporal lobe epilepsy is hip-

Glutamate transporters Glutamate transporters are expressed expressed by several several CNS cel celll typ types, es, but ast astroc rocyte ytess are pri primar marily ily res respon ponsib sible le for glutamatee uptake. glutamat uptake. Th Thee astroglial astroglial trans transporter porter GLT-1 GLT-1 is responsible for the clearance of bulk extracellular glutamate in the CNS, and increased extracellular levels of  glutamate have been found in epileptogenic foci. GLT-1 knockout in mice caused spontaneous seizures and hippocampal pathology resembling alterations in temporal lob lobee epi epileps lepsy y pat patien ients ts with with mes mesial ial tem tempor poral al scleros sclerosis. is. Several Seve ral human studies have supported the hypo hypothesis thesis that reduced or dysfunctional glial glutamate transporters in the hippocampus may trigger spontaneous seizures in

pocampal sclerosis, more generally termed mesial temporal sclerosis. Mesial temporal sclerosis is characterized by

patients with mesial temporal sclerosis ( Table 1), yet the underlying mechanisms are unclear.

Background and Results Glial Morphological Morphological Changes in Temporal Lobe Epilepsy 

Encyclopedia of Basic Epilepsy Research (2009), vol. 1, pp. 412-417

 

Glia/Astrocytes _  Role of Astrocyte Dysfunction in Epilepsy   413

  Table 1

 

Involv Involvement ement of astrogl astroglial ial membrane chann channels, els, transpo transporters rters,, and recep receptors tors in speci specific fic epilepsy syndro syndromes mes

Epilepsy syndrome

Astroglial molecule

Effect

Species

Methods

Temporal lobe epilepsy

No change No change #   No change #  

Human

IHC, WB, ISH

Human Hu

IHC

Human

IHC, ISH

Temporal lobe epilepsy

GLT-1 GLAST GLTGLT-1 1 GLAST GLTGLT-1 1 GLAST GLT-1

Human

IHC, WB,

Tempor Tem poral al lob lobe e epilep epilepsy sy

(Glu (Gluta tami mine ne synt synthe heta tase se)) GluR1 GluR1 (‘flip (‘flip’’ varian variant) t)  

( # )

Te Temp mpor oral al lobe lobe ep epile ileps psy y Te Temp mpor oral al lobe lobe ep epile ileps psy y

mG mGluR luR2/3 2/3 mGluR5 mGluR8 Ki Kirr ch chan anne nell Ki Kirr ch chan anne nell

Te Temp mpor oral al lobe lobe ep epile ileps psy y Temp Tempor oral al lobe lobe epil epilep epsy sy

Ki Kirr ch chan anne nell AQP4 AQP4

Fo Foca call co cort rtic ical al dysp dyspla lasi sia a

mGluR mGluR2/3 2/3 mGluR5 GLAST GLT-1 Kir chann hanne el

  " " " #     #   # #   "   overall #   perivascular   " " #   # #  

Te Temp mpor oral al lobe lobe ep epile ileps psy y Te Temp mpor oral al lobe lobe ep epile ileps psy y

Te Temp mpor oral al lobe lobe ep epile ileps psy y

Tuberous sclerosis Tuberous sclerosis

     

#

No change

                       

"

 

enzyme activity activity PC, pharmacology (CTZ, PEPA), single-cell rtPCR, RA  IHC

Human

Human Hu

Human Hu Human Rat (pilocarpine) Human Human

PC ISM, Ba2þ

Human Hu

IHC

PC, Ba2þ, single-cell rtPCR IHC, rtPCR, gene chip, EM

GFAP

WB WB,, PC

GFAP

PC PC,, WB, WB, Ba2þ, mRNA mRNA ana analysi lysis s

Tsc1

Tsc1

CKO mous mouse e CKO mous mouse e

Tumor-associated epilepsy Tumor-associated epilepsy Tumor-associated epilepsy Po Post sttr trau auma mati tic c ep epile ileps psy y

GluR2

 

#   Q/R editing

Human glioma

rtPCR, sequencing

GLT-1 GLAST Kir channel channel

 

#   Mislocalized #   Mislocalized #  

Human glioma

IHC

Human glioma

PC WB, IHC PC, ISM

Po Post sttr trau auma mati tic c ep epile ileps psy y

GLTGLT-1 1 GLAST

 

Ki Kirr an and d Kv chan channe nels ls  

 

  No change

#

Rat (fluid-percussion injury) Rat Rat (f (fer erro rous us ch chlo lori ride de))

WB

CTZ, cyclo cyclothiazi thiazide; de; EM, elect electron ron microscopy microscopy;; IHC, immunohist immunohistochem ochemistry; istry; ISH, in situ hybrid hybridizati ization; on; ISM, ion-sensitiv ion-sensitive e micro microelecelectrodes; trode s; PC, patch clamp; clamp; PEPA, 4-[2-(p 4-[2-(phenyl henylsulfony sulfonylamin lamino)eth o)ethylthio ylthio]-2,6-d ]-2,6-difluor ifluoro-phe o-phenoxya noxyacetam cetamide; ide; RA, restriction restriction analys analysis; is; rtPCR, rtPCR,   ¨  use er DK an and d St Stei einha nha userr C (20 (2006) 06)   Functional re reve vers rse e tr tran ansc scri ript ptas ase e polym polymer eras ase e ch chai ain n reac reacti tion on;; WB, WB, West Wester ern n bl blot ot.. Mo Modi difi fied ed from from Bind Binder changes change s in astrog astroglial lial cells in epile epilepsy. psy. Glia   54: 358–368.

Alternatively, alterations in glutamate metabolism may

GluR4. Combined functional and single-c single-cell ell transc transcript ript

be importan important. t. de Lane Laneroll rolle’ e’ss gro group up has foun found d red reduced uced glutamine synthet glutamine synthetase, ase, an enzyme enzyme in astrocy astrocytes tes that convert convertss glutamate into glutamine, in sclerotic rather than in nonsclerotic hippocampus of temporal lobe epilepsy patients (Table 1). Downregulation of glutamine synthetase would slow down glutamate–glutamine cycling and accumulation accumulation of the transmit transmitter ter in astrocyt astrocytes es and in the ext extrace racellula llularr space. This condition would provide a metabolic mechanism for astrocyte-dependent hyperexcitability.

analyses analys es reveale revealed d tha thatt enhanc enhanced ed expres expressio sion n of GluR1 GluR1 flip flip va vari rian ants ts ac acco count untss fo forr th thee pr prolo olong nged ed re recep cepto torr responses observed in hippocampal astrocytes of epilepsy patients with mesial temporal sclerosis ( Ta Table ble 1). Prolonged opening of receptor will promote influx of Ca2þ an and d Naþ ion ions. s. Ste Steinh inhaa¨user’s ¨user’s group group has shown shown tha thatt þ enhanced enhan ced intracellular intracellular Na blocks inwardly inwardly rectifying rectifying þ astroglial astro glial K (Kir) channels, further strengthening depolarizat larization ion and reduci reducing ng the Kþ buffe bufferin ringg capacit capacity y of  astrocytes, and thus contributing to hyperexcitability.

 Alterations of ionotropic glutamate receptors

 Metabotropic glutamate receptors and   astroglial Ca 2+  signalling in epilepsy 

A few studies have addressed the potential involvement of ionotropic glutamate receptors in seizure generation. Astrocytes Astro cytes abundantly express express receptors of the alphaamino-3-hy amino-3hydrox droxy-5-met y-5-methyl-4hyl-4-isoxaz isoxazoleprop olepropionic ionic acid (AMPA) sub (AMP subtyp typee compose composed d of the subunit subunitss GluR1 GluR1 to

mGluR3 and mGluR5 are the predominant metabotropic glutamate receptor subtypes expressed expressed by by glial cells. Activation of these receptors affects cAMP accumulation and lead leadss to an in incre creas asee in in intr trace acell llula ularr Ca2þ. Gr Grou oup p II

Encyclopedia of Basic Epilepsy Research (2009), vol. 1, pp. 412-417

 

414   Glia/Astrocytes  _  Role of Astrocyte Dysfunction in Epilepsy

 

mGluRs (mGluR 2, 3) have been shown to be coupled to cAMP levels in cultured astrocytes. mGluR-triggered rise in Ca2þ may cause oscillations and initiate Ca 2þ wave propagation within the astrocyte network, activate Ca 2þdependent depen dent ion channels, channels, and induce glutamate release from astrocytes. In experimental epilepsy, reactive astrocyte cytess of the the hi hipp ppoc ocamp ampus us pe persi rsist sten ently tly upre upregu gulat latee mGluR3, mGluR5, and mGluR8 protein. Electron microscopic and immunohistoch immunohistochemical emical inspection of hippo hippo--

taken up by glial cells. Any impairment of glial K þ uptake would be expected to be proconvulsant. In the hippocampus, millimolar and even submillimolar increases in extracellular Kþ concentration enhance epileptiform activity. High-Kþ also reliably induces epileptiform epileptiform activity in hippocampal hipp ocampal slices from human patients patients with intractable intractable temporal lobe epilepsy and hippocampal sclerosis. A primary mechanism for Kþ reuptake is thought to be via inwardly rectifying glial K þ channels (Kir channels).

campall ti campa tiss ssue ue from from te tempo mpora rall lobe lobe ep epile ileps psy y pati patien ents ts revealed reve aled expressio expression n of mGluR2/3 mGluR2/3,, mGluR4, mGluR5, and mGluR8 in reactive astrocytes, suggesting an involvement of these receptors in gliosis. Upregulation of astrogli glial al mGluR mGluR2/3 2/3 an and d mGluR mGluR55 was also also ob obse serv rved ed in epileptic specimens from patients with focal cortical dysplasia (Table Table 1). However, the functional role of glial mGluR upregulation in epilepsy is not yet clear.

Glial Kir channels may contribute to Kþ reuptake and spatial Kþ buffering, which has been most clearly demonstrated in the retina. Although multiple subfamilies of Kir channels exist (Kir1–Kir7) differing in tissue distribution and func functio tional nal pro proper pertie ties, s, the expres expression sion of Kir4.1 Kir4.1 in brain astrocytes has been investigated most thoroughly. Pharmacological or genetic inactivation of Kir4.1 leads to impairm imp airment ent of ex extra tracell cellular ular Kþ regulation. However, However, members of the strongly rectifying Kir2 family may also contribute contr ibute to astroglial astroglial Kþ buffering. Downregulat Down regulation ion of astrogli astroglial al Kir channels has been found in the injured or diseased CNS. Kir currents are reduced following injury-induced reactive gliosis  in vitro , entorhinal entor hinal cortex cortex lesion, lesion, freeze lesion-induced lesion-induced cortical dyspl dysplasia asia,, and tra traumat umatic ic and ischemi ischemicc brain brain injury injury.. In addition, several studies have indicated downregulation of Kir currents in specimens specimens from patients patients with temporal temporal lobe epilepsy epilepsy. Using ion-se ion-sensiti nsitive ve microelectrod microelectrodes, es, U. 2þ -sensitiv tivee Kþ Heineman Hein emann’ n’ss group group compare compared d glial Ba -sensi uptakee in the CA1 region of hippocampal uptak hippocampal slices obtained obtained from patients with or without mesial temporal sclerosis. Ba2þ, a blocke blockerr of Kir channels, channels, augmented augmented stimulusstimulusþ evoked K elevation in non-sclerotic but not in sclerotic specimens, suggesting an impairment in Kþ buffering in sclerotic tissue. Direct evidence for downregulation of Kir currents in the sclerotic CA1 region of hippocampus came from a comparative patch-clamp study in which a reduction in astroglial Kir currents was observed in sclerotic hippocampi compared with that in non-sclerotic hippo-

 Astrocytic Glutamate Release in Epilepsy 

Astrocytes are capable of releasing glutamate through a Ca2þ-dep -depend endent ent proces process, s, wh which ich cou could ld be inv involv olved ed in seizure generation. In chemically-induced, acute epilepsy models, it was recently reported that astrocytes contribute to the generation of synchronized epileptiform activity. In these the se studie studies, s, epi epilept leptifor iform m discha discharges rges we were re provok provoked ed thr through ough the app applica licatio tion n of 4-am 4-amino inopy pyrid ridine ine,, GAB GABA AA receptor recept or antag antagonist onists, s, or bath solutions containing low concentrations of divalent cations. It appeared that astrocytic increase in [Ca 2þ]i  is sufficient to stimulate release of glutamate from glial cells, which was critical for the generation of paroxysmal depolarization shifts (PDSs), a hallmar hallmark k of epilept epileptifor iform m act activi ivity ty.. In addit addition ion,, in viv vivo o imaging showed that some antiepileptic drugs suppressed astrocytic Ca2þ-signalling. An important caveat to these studies is that human epilepsy is associated with significant morphological alterations that are absent in acute

Table 1

models that have been studied.  Astrocyte Potassium and Water Channels

Since both extracellular Kþ concentration and osmolarity have been shown to markedly modulate neural excitability, it is plausible that changes in astrocytic K þ or water channels could contribute to hyperexcitability in epilepsy. Indeed, recent studies have found changes in astroglial Kir channels and AQP4 water channels in temporal lobe epilepsy specimens.

campi ( Kir channels ). These data underlie indicate that dysfunction of  astroglial astro glial channe ls could impaired Kþ buffering and contribute to hype hyperexc rexcitabilit itability y in epileptic epileptic tissue.. When sue When and ho how w thi thiss dy dysfun sfuncti ction on develo develops ps during during epileptogenesis is not yet clear. Water channels

During neuronal neuronal hyperacti hyperactivity vity,, extracellular extracellular [Kþ] may increase from   3 mM to a ceiling of 10–12 mM; and K þ

Alterations in astroglial water regulation could also highly affect exci excitability tability.. Brain tissue excitability excitability is extremely extremely sensitive to osmolarity and the size of the extracellular space (ECS). Decreasing ECS volume produces hyperexcitability and enhanced epileptiform activity; conversely, increa increasing sing ECS volume volume with with hypero hyperosmo smolar lar med medium ium att attenu enuate atess epi epilept leptifor iform m act activi ivity ty.. Th These ese ex exper perime imenta ntall data parallel extensive clinical experience indicating that

rel releas eased ed by active active neuron neuronss is tho thought ught to be primar primarily ily

hypo-osmolar states such as hyponatremia lower seizure

 K + channels

Encyclopedia of Basic Epilepsy Research (2009), vol. 1, pp. 412-417

 

 

Glia/Astrocytes _  Role of Astrocyte Dysfunction in Epilepsy   415

thr thresh eshold old wh while ile hypero hyperosmo smolar lar states states ele elevat vatee seizur seizuree threshold. The aquaporins (AQPs) are a family of membrane protei teins ns that that funct functionas ionas ‘wat ‘water er chann channels els’’ in man many y cel celll ty type pess and tiss tissues ues in wh which ich fluid transpo transport rt is crucia crucial.l. Aqua Aquapori porin-4 n-4 (AQP4) is expressed ubiquitously by glial cells, especially at specialized membrane domains including astroglial endfeet in contact with blood vessel vesselss and astrocyte membranes membranes that ensheat ensheath h glutamate glutamatergic rgic syn synapse apses. s. Act Activi ivity-i ty-induc nduced ed

 Astrocyte Dysfunction Involved in other Epilepsy  Syndromes

radial water fluxes in neocortex have been suggested to occur as a result result of water water movement movement via aquapor aquaporin in channel channelss in respons responsee to physiol physiologic ogical al acti activity vity.. Mice deficien deficientt in AQP4 have shown marked decrease in accumulation of  brain water (cerebral edema) following water intoxication and focal focal cerebral cerebral ischemia ischemia and impa impaired ired clearan clearance ce of brain water water in models models of va vasog sogenic enic edema, edema, sugg suggesti esting ng a function functional al role for AQP4 in brain water transport. Similarly, mice deficient in dystrophin or   a-syntrophin, in which there is mislocalization of the AQP4 protein, also show attenuated cerebral edema. Alteration in the expression and subcellular localization of AQP4 has been described in sclerotic hippocampi obtaine obt ained d from from patien patients ts with with mes mesial ial tem tempor poral al scle scleros rosis. is. One study using immunohistoch immunohistochemistry emistry,, rt-PCR, and gene chip analysis reported an overall increase in AQP4 expression in sclerotic hippocampi. However, using quantitative immunogold electron microscopy, the same group found foun d that that the there re wa wass misloca mislocaliza lizatio tion n of AQP4 AQP4 in the human epileptic hippocampus, with reduction in perivascularr membra cula membrane ne ex expre pressio ssion n (Tabl authors ors able e 1). The auth hypothesized that the loss of perivascular AQP4 perturbs buffer ferin ing, g, an and d re resul sults ts in an water ater flu flux, x, impair impairss Kþ buf increased propensity for seizures. Several lines of evidence support the hypothesis that AQP4 and Kir4.1 may act in concert in Kþ and H2O regulation. First, reuptake of Kþ into glial cells could be AQP4-dependent, as water influx coupled to Kþ influx is thought tho ught to unde underlie rlie activity activity-in -induce duced d glial cell swelli swelling. ng.

occ occurs urs inseizure 80–90% 80–90% of and case casessis of TS,medically frequentl frequently y involv involves es multiple types often refractory. Cortical tubers represent the pathologic substrate of TS, and microscopically consist of a specific type of dysplastic lesi lesion on wi with th as astr troc ocyt ytos osis is an and d abnorm abnormal al giant giant ce cells lls.. Although this suggests that astrocytes are involved in the pathologic lesion, in itself this is not the evidence for a causative role of astrocytes in TS epileptogenesis. However, recent evidence using astrocyte-specific  TSC1  conditio ditional nal kn knoc ocko kout ut mic micee has has pr prov ovid ided ed in insi sigh ghtt into into a potential role of astrocytes in the etiology of TS. These mice, which have conditional inactivation of the   TSC1 CKO O mice), genee in GFAPgen GFAP-exp expres ressing sing cells cells (Tsc1GFAPCK develop dev elop severe severe spontaneous spontaneous seizures by 2 months months of age and die prematurely. Intriguingly, the time point of onset

Tumor-associated epilepsy 

Second, studies inAQP4 the retina have subcellular co-locali co-lo calizati zation on of AQP 4 and Kir Kir4.1 4.1demonstrated via both electro electron n micromicroscopic sco pic and and co co-im -immun munop oprec recipi ipita tatio tion n ana analys lyses. es. Third, hird, / / Kir4.1 mice, like AQP4 mice, have impaired retinal and cochlear physiology presumably due to altered K þ metabolism. Fourth, AQP4/ mice have remarkably slowed Kþ reup reuptak takee in models models of seiz seizure ure and spreadi spreading ng depression depress ion in vivo associated associated with a near-threefold near-threefold increase in seizure seizure duratio duration. n. Fift Fifth, h, afferent afferent stimulati stimulation on of hippocam hippocam-pal slices from a-syntrophin-deficient mice demonstrates a deficit in extracellular Kþ clearance. The These se data are consistent with the idea that AQP4 and Kir4.1 participate in clearance of Kþ following neural activity. However, further studies are required to clarify the expression and functional inter interact action ion of AQP4 AQP4 and Kir4.1 Kir4.1 in the bra brain in and and their their

Tumor-associated epilepsy is an important clinical problem, seen in approximately one-third of cases. Surgical remov rem oval al of tumors tumors usua usually lly res result ultss in seizure seizure con contro trol, l, but many tumors cannot safely be resected, and tumorassociated seizures are often resistant to anticonvulsant therapy. Classic epilepsy-associated brain tumors include astrocytoma, astroc ytoma, oligodendrogliom oligodendroglioma, a, ganglioglioma, dysem dysem-bryoplastic neuroepithelial tumor, and pleomorphic xanthoastr tho astrocy ocytoma toma.. Microdia Microdialys lysis is studies studies of gliomas gliomas have have reveale rev ealed d reduced reduced glutamat glutamatee in the tumor compared compared to peri-tu per i-tumor moral al tiss tissue. ue. A ‘glutamat ‘glutamatee hypothe hypothesis’ sis’ of tumortumorassociated epilepsy has been advanced which suggests that tumors excite surrounding tissue by glutamate overstimulation. Two lines of evidence are relevant relevant to this hypothesis. Fir First st,, theglutama theglutamate te rec recept eptor or subun subunit it GluR2 GluR2 hasbeen found found

changes during epileptogenesis.

to be underedited at the Q /R site in gliomas, g liomas, which would would

Tuberous sclerosis

Tuberous sclerosis (TS) is a multisystem genetic disorder resulting from autosomal dominant mutations of either TSC1 or  TSC2  genes. The  TSC1  gene encodes the protein hamartin and   TSC2  encodes tuberin, which are thought to be regulators of cell signalling and growth. Epilepsy

of spontaneous seizures in these mice is concordant with increased astroglial proliferation. Furthermore, two functions of astrocytes – glutamate and Kþ reuptake – are impaire imp aired d in these these mice. mice. These These mice displa display y reduced reduced expression of the astrocyte glutamate transporters GLT1 and GLAST. In addition, recent evidence indicates that astrocytes from  Tsc1GFAPCKO mice exhibit reduced Kir channe cha nnell act activi ivity ty,, and hippoc hippocamp ampal al sli slices ces fro from m these these þ mice demonstrated increased sensitivity to K -induced epileptiform activity (Table Table 1). Together, these studies demonstrate that in this model, changes in glial properties may be a direct cause of epileptogene epileptogenesis. sis.

Encyclopedia of Basic Epilepsy Research (2009), vol. 1, pp. 412-417

 

416   Glia/Astrocytes  _  Role of Astrocyte Dysfunction in Epilepsy

 

potentialalincrease AMPA receptor Ca2þ permeability and potenti ly res result ult in inc increas reased ed gluta glutamate mate release release by glioma cells (Table 1). Second, glioma cells release larger than normal amounts of glutamate   in vitro . The release of glutamate from glioma cells is accompanied by a marked deficit in Naþ-dependent glutamate uptake, reduced expression of  astrocy astr ocytic tic glut glutamat amatee transpo transporters rters,, and upre upregula gulation tion of  cystine-glutamate cystin e-glutamate exchange (Table 1). Hence, glioma cell glutamate release at the margins of the tumor may initiate

sclerotic hippocampi from patients with temporal lobe epi epileps lepsy y or animal animal mod models els res resemb emblin lingg thi thiss particu particular lar human condition. However, the various functions of astrocytes in modulation of synaptic transmission and glutama mate te,, Kþ and and H2O reg regulat ulation ion sugges suggestt that that ast astroc rocyte yte dysfunction could also be part of the pathophysiology of  other forms of epilepsy. One important recent dev developme elopment nt is the recognition of st struc ructu tura rall an and d funct functio iona nall he hete terog rogen eneit eity y of ce cells lls

seizures in peritumoral neurons. A distinct potential mechanism underlying tumor-associated epilepsy is altered Kþ homeost home ostasis asis.. In support support of this hyp hypoth othesis esis,, both reduced reduced Kir currents and mislocalization of Kir4.1 channels have been found in malignant astrocytes astrocytes ( Table 1).

with wi th as astr trogl oglia iall pr prop opert erties ies.. It is cle clear ar th that at a su subs bset et of  hippocamp hippoc ampal al ast astrogl roglial ial cell cellss (‘class (‘classical ical’’ ast astroc rocyte ytess or GluT Glu T cells) cells) ex expre presse ssess glutamat glutamatee tra transp nsporte orters rs and not ionotropic glutamate receptors and another (NG2 glia or GluR cells) expresses ionotropic glutamate receptors but not glutamat glutamatee tra transp nsporte orters. rs. Howev However er,, the lineage lineage rel relatio ationsh nship ip of NG2 glia/Glu glia/GluR R cells cells and the rel relati ative ve roles of  bona   bona fide  astrocytes   astrocytes versus NG2 glia/GluR cells in epilepsy still remain unclear. In addition, the functional roles of ionotropic glutamate receptors, Kir and AQP4 channels in these subsets of glial cells in the hippocampus are not yet understo understood. od. Hippocampal NG2 glia/GluR cel cells ls lack gap junctiona junctionall coupling coupling but rec recei eive ve direct direct synaptic input from GABAergic and glutamatergic neuro rons ns.. Ga Gap p juncti junction onss ma may y als also o re regul gulat atee ex excit citabi abilit lity y, althou although gh av availa ailable ble dat dataa are inc incons onsist istent ent regard regarding ing the impact of altered altered connexin connexin expressio expression n on epilept epileptogenogenesis. The availability of mice with genetically uncoupled ast astroc rocyte ytess will allo allow w ex examin aminatio ation n of thi thiss questi question, on, by separating the effects produced by alterations of neuronal versus versus glial glial gap junct junction ions. s. It will be imp importa ortant nt in fut future ure stu studie diess to examine examine the cel cellula lularr and molecul molecular ar properties of subsets of hippocampal glial cells in human epileptic tissue and unravel the course of their functional alterations during epileptogenesis in appropriate animal models. Anothe Ano therr recent recent foc focus us in ast astroc rocyte yte biology biology tha thatt may become important for epilepsy research is the ‘gliovascular junction.’ Microvascular proliferation in the sclerotic

 Posttraumatic epilepsy 

Posttraumatic epilepsy refers to a recurrent seizure disorder whose cause is believed to be traumatic brain injury. It is a common and important form of epilepsy, epilepsy, and develops in a variable proportion of traumatic brain injury survivors depending on the severity of the injury and the time after injury. Anticonvulsant prophylaxis is ineffective at preventing the occurrence of late seizures. Weight-drop and fluid-percussion injury animal models of posttraumatic epilepsy epilepsy have have demonstrate demonstrated d charact characteristic eristic structural and functional changes in the hippocampus, such as death of dentate hilar neurons and mossy fiber sprouting.. Recently outing Recently,, studies studies have also implicated implicated alter altered ed ast astroc rocyte yte fun functio ction n in posttr posttraum aumatic atic epi epileps lepsy y models. models. Recordings from glial cells in hippocampal slices 2 days after fluid-percussion injury demonstrated reduction in transient outward and inward Kþ currents (Table 1), and antidromic stimulation of CA3 led to abnormal extracellular Kþ accumulation in posttraumatic slices compared to controls. This was accompanied by the appearance of  electrical afterdischarges in CA3. Thus, this study suggests impaired Kþ homeostasis in posttraumatic hippocampal glia. Another Another study study demonstrated demonstrated reduction in expression of the astrocyte glutamate transporter GLT1 in a posttraumatic posttraumatic epilepsy model induced by intracortiintracortical ferrous chloride injection ( Table Table 1), suggesting impaired glutamate transport. Further studies of the role of  glial cells in posttraumatic epilepsy appear warranted warranted now that reliable posttraumatic epilepsy animal models have been developed.

Astroc Ast rocyte ytess underg undergo o cellula cellularr and mol molecul ecular ar cha change ngess in epilepsy, including epilepsy, including alteration alteration in glutamate transporte transporters rs and receptors as well as Kir chann channels els and water channels.

hippocampus was noted as early as 1899, but the role of  the vasculature vasculature and the blood-brain blood-brain barrier in epilepsy is not yet clear. The intimate relationship between astroglial endfeet ensheathing blood vessels, the targeted expression of AQP4 and Kir4.1 on astroglial endfeet, and the role of  astrocytes in blood-brain barrier permeability and control of microcirculation have only recently been appreciated. Local pathological alterations in the gliovascular junction could perturb blood flow, Kþ and H2O regulation and constitute an important mechanism in the generation of  hyperexc hype rexcitabilit itability y. Indeed, Indeed, a recent recent study study suggests suggests that transient opening of the blood-brain barrier is actually sufficie suff icient nt for foc focal al epi epilept leptoge ogenes nesis. is. The cellular cellular and molecular roles of the gliovascular junction in metabolic homeostasis and changes during epileptogenesis are only

So far, most of these changes have been demonstrated in

beginning to be explored.

Perspectives and Future Directions

Encyclopedia of Basic Epilepsy Research (2009), vol. 1, pp. 412-417

 

 

Glia/Astrocytes _  Role of Astrocyte Dysfunction in Epilepsy   417

In conclusion, the exact changes taking place in astroglial functioning during epilepsy are still poorly understood. stoo d. Th Thee term ‘rea ‘reacti ctive ve gliosis’ gliosis’ is too des descrip cripti tive ve and should be replaced by careful morphological, biochemical, and electrop electrophys hysiolo iological gical studies studies of identifi identified ed glial cell subtypes in human tissue and animal models. In addition to changes changes in preexi preexistin stingg glial cell popu populati lations ons,, newlynewlygenerated glial cells with distinct properties may migrate into the hippocampus and contribute to enhanced seizure suscepti susc eptibilit bility y. Th Thee av availab ailable le dat dataa likely likely repr represe esent nt onl only y the ‘tip of the iceberg’ iceberg’ in te terms rms of the the fun functi ctiona onall ro role le of astroglial cells in epilepsy. In view of the many physiologic functions functions of astr astrocy ocytes tes that have have been elucida elucidated ted within the past decade, it can be expected that the next few years of research will yield evidence of similar important roles roles for glial cells in pathoph pathophysio ysiology logy.. Further Further stud study y of  astrocyte astroc yte alterations in epilepsy should lead to the identification catio n of novel novel molecular molecular targets targets that might open new avenues for the development of alternative antiepileptic therapies.

Further Reading Binder DK and Steinha¨ user C (2006 ) Functional changes in astroglial cells in epilepsy. Glia epilepsy.  Glia 54:  54: 358–368. During MJ and Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain.  Lancet  341:   341: 1607–1610. Eid T, Thom Thomas as MJ, Spenc Spencer er DD, Runde Runden-P n-Pran ran E, Lai JC, Maltha Mal thanka nkarr GV, Kim JH, Danbol Danboltt NC, Otter Ottersen sen OP, and de Lanerolle Lane rolle NC (2004) Loss of gluta glutamine mine synthe synthetase tase in the human epileptoge epile ptogenic nic hippoc hippocampus: ampus: Possible mechanism mechanism for raise raised d

  Glia/Astrocytes: As Astr troc ocyt ytic ic Regu Regula lati tion on of  Neuronal Neuro nal Excita Excitabilit bility; y; Glial Modulation Modulation of Excita Excitability bility via Glutamate Gluta mate and GABA Transporters; Transporters; Glial-Medi Glial-Mediated ated Mechan chanis isms ms of Epil Epilep epto toge gene nesi sis s in Tu Tube bero rous us Sc Scle lero rosi sis; s; Peri Peritu tumo mora rall Epil Epilep epsy sy;; Prop Proper erti ties es of Glia Glia in Epil Epilep epti tic c Brain; Tumor-Induced Epilepsy and Epileptogenic Potential tial of Bra Brain in Tum Tumor or Treatm Treatment ent;;   Neurotrophic Factors:

extracell extra cellular ular gluta glutamate mate in mesia mesiall tempor temporal al lobe epile epilepsy. psy.   Lancet  363: 28–37. Hinterkeuser S, Schro  ¨ der  ¨ der W, Hager G, Seife Seifert rt G, Blu  ¨ mcke  ¨ mcke I, Elger CE, Schramm J, and Steinha  ¨ user  ¨ user C (2000) Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. The conductances.  The European Journal of  Neuroscience 12: Neuroscience  12: 2087–2096 2087–2096.. Jansen LA, Uhlmann EJ, Crino PB, Gutmann DH, and Wong M (2005) Epileptogenesis and reduced inward rectifier potassium current in tuberous sclerosis complex-1-deficient astrocytes. Epilepsia astrocytes.  Epilepsia 46:  46: 1871–1880. Kivi A, Lehmann TN, Kovacs R, Eilers A, Jauch R, Meencke HJ, von Deimling A, Heinemann U, and Gabriel S (2000) Effects of barium on stimulus-induced rises of [K þ]  in human epileptic non-sclerotic and sclerotic hippocampal area CA1. The CA1.  The European Journal of  Neuroscience 12: Neuroscience  12: 2039–2048 2039–2048.. Matthias K, Kirchhoff F, Seifert G, Hu  ¨ ttmann  ¨ ttmann K, Matyash M, Kettenmann H, and Steinha  ¨ user  ¨ user C (2003) Segregat Segregated ed expre expression ssion of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus.  Journal of Neuroscience Neuroscience 23:  23: 1750–175 1750–1758. 8. Schwartzkroin PA, Baraban SC, and Hochman DW (1998) Osmolarity, ionic flux, and changes in brain excitability. Epilepsy excitability.  Epilepsy Research 32: Research  32: 275–285. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, and Friedman Friedman A (2004) Last Lasting ing blood-br blood-brain ain barri barrier er disrup disruption tion induces induces epileptic focus in the rat somatosensory cortex.  Journal of  Neuroscience 24: Neuroscience  24: 7829–783 7829–7836. 6.  ¨ user  ¨ user C (2004) Seifert G, Hu¨ ttmann K, Schramm J , and S teinha Enhanced relative expression of glutamate receptor 1 flip AMPA  receptor subunits in hippocampal astrocytes of epilepsy patients with Ammon’s horn sclerosis. Journal sclerosis.  Journal of Neuroscience 24: Neuroscience  24: 1996–2003. Steinha  ¨ user  ¨ user C and Seifert G (2002) Glial membrane channels and receptors in epilepsy: Impact for generation and spread of seizure activity. European activity.  European Journal of Pharmacology  447:   447: 227–237.  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 astrocytic

Role of BDNF Role BDNF in Ani AnimalModel malModels s of Epi Epilep lepsy; sy; Non-Synaptic Changes in Extra Extracellu cellular lar Ion Compos Composition ition;; Mechanisms: Changes Ch Chan ange ges s in Ex Extr trac acel ellu lula larr Sp Spac ace e as a Mo Modu dula lato torr of  Excitability Excita bility and Epile Epileptogen ptogenicity icity;; Modulation Modulation of Neur Neuronal onal Excitability Excita bility by Chan Changes ges in Extra Extracellu cellular lar Ion Compos Composition ition;; Role Role of Aqua Aquapor porin ins s in No Nonn-Sy Syna napti ptic c Me Mech chan anis isms ms of  Epilepsy;  Transporters: Fun Functi ction on of Cel Cell-S l-Surf urface ace GlutaGlutamate mate Tran Transpo sport rter ers s in th the e Brai Brain: n: An Im Impo port rtan antt Role Role fo forr Development and Preventing Seizures.

basis of epilepsy. Nature epilepsy.  Nature Medicine 11: Medicine  11: 973–981.  ¨ user  ¨ user C (2004) Glial modulation of synaptic  Volterra A and Steinha transmission in the hippocampus. Glia hippocampus.  Glia 47:  47: 249–257. Wallraff A, Kohling R, Heinemann U, Theis M, Willecke K, and  ¨ user  ¨ user C (2006) The impact of astrocytic gap junctional Steinha coupling on potassium buffering in the hippocampus. Journal hippocampus.  Journal of  Neuroscience 26: Neuroscience  26: 5438–5447 5438–5447..  Ye ZC, Rothstein JD, and Sontheimer H (1999) Compromised glutamate transport in human glioma cells: Reductionmislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. Journal exchange.  Journal of  Neuroscience   19: 10767–10777. Neuroscience

 Acknowledgements D. D.K.B K.B.. is support supported ed by a Ame America rican n Epi Epileps lepsy y Societ Society/ y/ Milken Family Foundation Early Career Physician Scientist Award. C.S. is supported by grants from the Deutsche Forschungsgemeinschaft (SFB/TR3; SPP1172). We apologizee to all those ogiz those wh whose ose work could not be discuss discussed ed because of space constraints. Se See e

al also so::

o

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