Glia And Epilepsy: Excitability And Inflammation

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ReviewGlia and epilepsy: excitabilityand inflammationOrrin Devinsky1, Annamaria Vezzani2, Souhel Najjar1, Nihal C. De Lanerolle3, andMichael A. Rogawski41Epilepsy Center, Department of Neurology, NYU School of Medicine, New York, NY 10016, USADepartment of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy3Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA4Department of Neurology, University of California, Davis School of Medicine, Sacramento, CA 95817, USA2Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony ofbrain neurons. Current theories of pathophysiologystress neuronal dysfunction and damage, and aberrantconnections as relevant factors. Most antiepileptic drugstarget neuronal mechanisms. However, nearly one-thirdof patients have seizures that are refractory to availablemedications; a deeper understanding of mechanismsmay be required to conceive more effective therapies.Recent studies point to a significant contribution by nonneuronal cells, the glia – especially astrocytes and microglia – in the pathophysiology of epilepsy. This reviewcritically evaluates the role of glia-induced hyperexcitability and inflammation in epilepsy.IntroductionGlia outnumber neurons in the cerebral cortex by morethan 3:1 by some estimates [1], with oligodendrocytescomprising approximately 75% of cortical glia, followedby astrocytes ( 17%) and microglia ( 6.5%) [2]. Glia areintimately involved in diverse neuronal functions: guidingmigration during development; modulating synaptic function and plasticity; regulating the extracellular microenvironment by buffering neurotransmitter, ion, and waterconcentrations; insulating axons; regulating local bloodflow and the delivery of energy substrates; contributingto the permeability functions of the blood–brain barrier(BBB) [3,4]; and enforcing cellular immunity in the brain torestore function and promote healing [5]. These physiological functions of normal glia help to maintain tissuehomeostasis.Dysregulation of glial functions may cause seizures orpromote epileptogenesis [6]. Abnormal glia, includingchronically activated astrocytes and microglia, glial scars,and glial tumors, are a prominent feature of epileptic foci inthe human brain and in experimental epilepsy models. Themajor mechanisms by which glia can facilitate the development of seizures and epilepsy include increased excitability and inflammation. Disruption of glial-mediatedregulation of ions, water, and neurotransmitters can promote hyperexcitability and hypersynchrony. Uncontrolledglial-mediated immunity can cause sustained inflammatoryCorresponding author: Devinsky, O. ([email protected])Keywords: glia; epilepsy; neuroinflammation; astrocyte; microglia.174changes that facilitate epileptogenesis. This review examines how glial-mediated changes in excitability and inflammation contribute to epilepsy.Reactive astrocytosis and the epileptic focusAstrocytes undergo changes in morphology, molecularcomposition, and proliferation in epileptic foci. This ‘reactive astrogliosis’ process includes a continuous spectrum ofchanges that vary with the nature and severity of diverseinsults [7]. Reactive astrocytes occur in animal models ofepilepsy and in brain tissue from patients with mesialtemporal sclerosis (MTS), focal cortical dysplasia (FCD),tuberous sclerosis complex (TSC), Rasmussen’s encephalitis, or glioneuronal tumors [8–10]. Interestingly, astrocytesare a specific target of cytotoxic T cells in Rasmussen’sencephalitis, an epilepsy with chronic brain inflammation[7,9]. MTS, the most common pathology associated withtemporal lobe epilepsy (TLE), is characterized by astroglialand microglial activation and proliferation [6], with increased complexity and arborization of astroglial processes[11], often approaching glial scar-like formations in latestage MTS. In epileptic brain, reactive astrocytes exhibitphysiological and molecular changes, such as reducedinward rectifying K current or changes in transportersor enzyme systems that may underlie epileptic hyperexcitability (Figure 1).Water and K bufferingAstrocytes regulate water and K flow between brain cellsand the extracellular space (ECS). Neuronal excitability istightly coupled to ECS K levels and ECS volume. The ECSis reciprocally related to neuronal and glial cell volumes.Increased ECS and decreased neuronal/glial cell volumereduces excitability. Low-osmolarity solutions contract theECS and promote epileptic hyperexcitability [12]. Indeed,water intoxication can cause seizures, particularly ininfants. Shrinking the ECS may promote seizures by increasing extracellular K concentrations and possibly byenhancing ephaptic (non-synaptic) neuronal interactions.The diuretics furosemide and bumetanide mediate antiepileptic effects by reducing cell volume by blocking the glialNa–K–2Cl cotransporter [13].The glial water channel aquaporin-4 (AQP4) is implicated in the pathogenesis of epilepsy [14]. AQP4 mediatesthe bidirectional flow of water between the ECS and the0166-2236/ – see front matter ß 2012 Elsevier Ltd. All rights reserved. Trends in Neurosciences, March 2013, Vol. 36, No. 3

ReviewTrends in Neurosciences March 2013, Vol. 36, No. 3H2OCapillaryK Ca2 waves96 GlutaminesynthetaseGlutamate Kir4.1EAAT1/EAAT27510H2OK Ac onpoten alPresynap cneuron21Synap cvesiclesNa Gliotransmi ersGlutamate, D-serine, ATP,adenosine, GABA, TNFα4AMPA-RNa K Reac veastrocyte3NMDA-RNa Ca2 Postsynap cneuronEpilep formdischargeTRENDS in NeurosciencesFigure 1. Schematic model depicting selected interactions between astrocytes and excitatory neurons. Voltage-gated Na and K channels (1) generate action potentials inthe presynaptic neuron, leading to the exocytotic synaptic release of neurotransmitter glutamate (2). Glutamate activates AMPA and NMDA receptors (3) in the postsynapticmembrane, causing excitatory synaptic potentials generated by influx of Na and Ca2 . If sufficiently strong, synaptic excitation leads to epileptiform discharges (4).Glutamate is taken up into reactive astrocytes by the EAAT1 (GLAST) and EAAT2 (GLT-1) transporters (5) and is converted to glutamine by glutamine synthetase (6).Glutamine is a substrate for the production of GABA in inhibitory GABAergic neurons (not shown). Loss of glutamine synthetase in reactive astrocytes leads to a decrease inGABA production. K released from neurons by voltage-gated (outwardly rectifying) K channels enters astrocytes via inwardly rectifying K channels (Kir4.1) (7) and isdistributed into capillaries. Aquaporin-4 (AQP4) concentrated at astrocytic endfoot processes regulates water balance (8). Ca2 waves (9) stimulate the release ofgliotransmitters (10) that can influence neuronal excitability. The inhibitory substance adenosine is taken up into astrocytes by the equilibrative nucleoside transportersENT1 and ENT2 and concentrative nucleoside transporter CNT2. Excessive adenosine kinase in reactive astrocytes increases the removal of adenosine (11), enhancinghyperexcitability.blood, thus regulating interstitial fluid osmolarity and ECSvolume. Mice lacking AQP4 or components of the dystrophin-associated protein complex that anchors AQP4, including a-syntrophin and dystrophin, have altered seizuresusceptibility, and epilepsy can complicate human muscular dystrophy affecting the dystrophin complex [10,14]. InMTS specimens, AQP4 is redistributed from perivascularglia endfeet to the perisynaptic space [15]. This may enhance water entry into the neuropil but impair wateregress into the perivascular space, swelling astrocytes,contracting the ECS, and increasing excitability [6]. Thus,glial AQP4 dysfunction can impair water delivery to theECS, increasing susceptibility to seizure [16].Glia provide an osmotically neutral spatial bufferingsystem for K using inward rectifying K channels (Kir)that carry K ions into cells accompanied by water entrythrough AQP4 to maintain osmotic balance. Excessivelocal concentrations of K predispose to seizures [17];impaired glial buffering may help cause epilepsy [18].Conditional knockout of Kir4.1 depolarizes glial membranes, inhibits potassium and glutamate uptake, andpotentiates synaptic strength [19]. Reduced Kir4.1 expression (but not other K channels) increases extracellular K in a BBB disruption model of epileptogenesis [19]. In thekainic acid-induced status epilepticus model, AQP4 ismarkedly reduced, suggesting that impaired water andpotassium homeostasis occurs early in epileptogenesisand providing a potential therapeutic target [20]. Moreover,murine and human polymorphisms or mutations ofKCNJ10, which encodes the astroglial Kir4.1 K channel,are associated with epilepsy [21]. Because Kir4.1 dysfunction can compromise K spatial buffering [22], both acquiredand genetic epilepsies could result from glial pathology.Impaired Kir channel function in the CA1 region in MTSsuggests that this pathological mechanism is clinically relevant [23,24]. Impaired gap junction coupling between astrocytes may also disrupt spatial K buffering, but this remainscontroversial [6,21]. The homeostatic role of astrocytesextends from ions and water balance to neurotransmitterlevels and maintaining BBB function.Regulating neurotransmissionGlutamate uptake by high-affinity membrane transportersis essential for maintaining low ambient levels of glutamate. Uptake is of particular importance when there isintense excitatory synaptic activity, as occurs during epileptic discharges. Uptake mechanisms prevent spill-out oftransmitter from the synaptic cleft, thus regulating crosstalk between neighboring synapses and the activation ofperisynaptic/extrasynaptic glutamate receptors. Five glutamate transporters are present in the brain. GLAST andGLT-1 (human forms: EAAT1 and EAAT2, respectively)are expressed in glial cells, primarily astrocytes. Thesetransporters, which have an affinity for glutamate of2–90 mM, are densely concentrated in hippocampal astrocyte membranes [25,26]. As soon as a vesicle releases its175

Reviewload of glutamate into the synapse, most of the glutamateis removed from the ECS by astrocytic transporters. Astrocytes are optimized for glutamate uptake due to their high(negative) resting potential, which enhances the sodiumelectrochemical gradient that drives transport, and lowcytoplasmic glutamate concentration. Do astrocytic glutamate transporters restrain epileptic activity under normal or pathological conditions? Although antisenseknockdown of the neuronal glutamate transporter EAAC1leads to epilepsy (due to reduced GABA synthesis), knockdown of the astrocyte glutamate transporter GLT-1 doesnot [27]. However, mice with genetic knockout of GLT-1display increased levels of synaptic glutamate in responseto stimulation and exhibit spontaneous lethal seizures,and seizures in response to ordinarily subconvulsive dosesof pentylenetetrazol [28]. Moreover, in rats with corticaldysplasia-like lesions, dihydrokainate, a selective inhibitor of GLT-1, decreased the threshold for inducing epileptiform activity [29]. Interestingly, in a BBB disruptionepileptogenesis model, GLAST and GLT-1 (but notEAAC1) were downregulated and there was electrophysiological evidence of reduced glutamate buffering [30].In TLE, both normal and reduced expression of theastroglial glutamate transporters EAAT1 and EAAT2were found [119]. Therefore, in some instances impairedglutamate uptake by astrocytes may increase epileptichyperexcitability. Astrocyte glutamate uptake capacity isenhanced by activating astroglial metabotropic glutamatereceptors (mGluRs) [31]. In MTS and FCD, astroglialmGluRs are upregulated [6,8,32], suggesting a compensatory response to prevent seizures. The role of astrocytemembrane transporters in regulating epileptic activityremains suggestive but unproven. Similarly, accumulatingevidence suggests that cytoplasmic astrocyte enzymes helpmaintain excitatory/inhibitory neurotransmitter homeostasis [33–43]. Examples are provided by adenosine kinase(ADK) and glutamine synthetase (GS).ADK is a predominantly astrocytic enzyme that regulates brain extracellular adenosine levels by phosphorylating adenosine to form 50 -adenosine monophosphate.Astrogliosis in animal models of epilepsy is associatedwith increased levels of ADK. Adenosine is a powerfulinhibitory substance released during seizures and implicated in seizure arrest, postictal refractoriness, and suppression of epileptogenesis [33]. Astrogliosis-mediatedincreased ADK expression may lower the seizure threshold by reducing extracellular adenosine. This concept issupported by studies showing that; (i) pharmacologicalinhibition of ADK suppresses seizures; (ii) upregulation ofADK is associated with spontaneous seizures in a model ofepileptogenesis; and (iii) resistance to epileptogenesisoccurs in transgenic mice with reduced forebrain ADK[34]. Interestingly, ADK is overexpressed in human glialtumor tissue and the peritumoral region infiltrated byglia, suggesting that reduced adenosine could play a rolein the development of epilepsy in patients with glialtumors [35]. ADK expression levels are also increasedin the seizure foci of TLE patients [36]. Basal adenosineis reduced in epileptic compared with control humanhippocampus, consistent with ADK contributing toepileptogenesis [36].176Trends in Neurosciences March 2013, Vol. 36, No. 3GS, a cytoplasmic enzyme found predominantly inastrocytes, is critical to glutamate homeostasis [37]. GScatalyzes the ATP-dependent condensation of glutamatewith ammonia to yield glutamine. The observation that GSlevels are significantly reduced in the human hippocampusand amygdala in TLE suggested a role for the enzyme inepileptogenesis [37]. Transient elevations in extracellularglutamate occur during seizures in these and other brainregions, but ambient glutamate levels are also incr