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Glia and Epilepsy: Excitability

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Glia and Epilepsy: Excitability Review Glia and epilepsy: excitability and inflammation 1 2 1 3 Orrin Devinsky , Annamaria Vezzani , Souhel Najjar , Nihal C. De Lanerolle , and 4 Michael A. Rogawski 1 Epilepsy Center, Department of Neurology, NYU School of Medicine, New York, NY 10016, USA 2 Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy 3 Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA 4 Department of Neurology, University of California, Davis School of Medicine, Sacramento, CA 95817, USA Epilepsy is characterized by recurrent spontaneous sei- changes that facilitate epileptogenesis. This review exam- zures due to hyperexcitability and hypersynchrony of ines how glial-mediated changes in excitability and inflam- brain neurons. Current theories of pathophysiology mation contribute to epilepsy. stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs Reactive astrocytosis and the epileptic focus target neuronal mechanisms. However, nearly one-third Astrocytes undergo changes in morphology, molecular of patients have seizures that are refractory to available composition, and proliferation in epileptic foci. This ‘reac- medications; a deeper understanding of mechanisms tive astrogliosis’ process includes a continuous spectrum of may be required to conceive more effective therapies. changes that vary with the nature and severity of diverse Recent studies point to a significant contribution by non- insults [7]. Reactive astrocytes occur in animal models of neuronal cells, the glia – especially astrocytes and micro- epilepsy and in brain tissue from patients with mesial glia – in the pathophysiology of epilepsy. This review temporal sclerosis (MTS), focal cortical dysplasia (FCD), critically evaluates the role of glia-induced hyperexcit- tuberous sclerosis complex (TSC), Rasmussen’s encephali- ability and inflammation in epilepsy. tis, or glioneuronal tumors [8–10]. Interestingly, astrocytes are a specific target of cytotoxic T cells in Rasmussen’s Introduction encephalitis, an epilepsy with chronic brain inflammation Glia outnumber neurons in the cerebral cortex by more [7,9]. MTS, the most common pathology associated with than 3:1 by some estimates [1], with oligodendrocytes temporal lobe epilepsy (TLE), is characterized by astroglial comprising approximately 75% of cortical glia, followed and microglial activation and proliferation [6], with in- by astrocytes (17%) and microglia (6.5%) [2]. Glia are creased complexity and arborization of astroglial processes intimately involved in diverse neuronal functions: guiding [11], often approaching glial scar-like formations in late- migration during development; modulating synaptic func- stage MTS. In epileptic brain, reactive astrocytes exhibit tion and plasticity; regulating the extracellular microenvi- physiological and molecular changes, such as reduced + ronment by buffering neurotransmitter, ion, and water inward rectifying K current or changes in transporters concentrations; insulating axons; regulating local blood or enzyme systems that may underlie epileptic hyperexcit- flow and the delivery of energy substrates; contributing ability (Figure 1). to the permeability functions of the blood–brain barrier + Water and K buffering (BBB) [3,4]; and enforcing cellular immunity in the brain to + Astrocytes regulate water and K flow between brain cells restore function and promote healing [5]. These physiolog- and the extracellular space (ECS). Neuronal excitability is ical functions of normal glia help to maintain tissue + homeostasis. tightly coupled to ECS K levels and ECS volume. The ECS is reciprocally related to neuronal and glial cell volumes. Dysregulation of glial functions may cause seizures or Increased ECS and decreased neuronal/glial cell volume promote epileptogenesis [6]. Abnormal glia, including reduces excitability. Low-osmolarity solutions contract the chronically activated astrocytes and microglia, glial scars, ECS and promote epileptic hyperexcitability [12]. Indeed, and glial tumors, are a prominent feature of epileptic foci in water intoxication can cause seizures, particularly in the human brain and in experimental epilepsy models. The infants. Shrinking the ECS may promote seizures by in- major mechanisms by which glia can facilitate the devel- + creasing extracellular K concentrations and possibly by opment of seizures and epilepsy include increased excit- enhancing ephaptic (non-synaptic) neuronal interactions. ability and inflammation. Disruption of glial-mediated The diuretics furosemide and bumetanide mediate antiep- regulation of ions, water, and neurotransmitters can pro- ileptic effects by reducing cell volume by blocking the glial mote hyperexcitability and hypersynchrony. Uncontrolled Na–K–2Cl cotransporter [13]. glial-mediated immunity can cause sustained inflammatory The glial water channel aquaporin-4 (AQP4) is impli- cated in the pathogenesis of epilepsy [14]. AQP4 mediates Corresponding author: Devinsky, O. ([email protected]) Keywords: glia; epilepsy; neuroinflammation; astrocyte; microglia. the bidirectional flow of water between the ECS and the 174 0166-2236/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2012.11.008 Trends in Neurosciences, March 2013, Vol. 36, No. 3 Review Trends in Neurosciences March 2013, Vol. 36, No. 3 + Capillary H2O K Endfoot AMP 8 Glutamine Ca2+ waves Adenosine 11 kinase 6 Glutamine 9 Reacve Adenosine synthetase astrocyte Glutamate AQP4 Kir4.1 EAAT1/ EAAT2 7 5 10 H2O Gliotransmiers Glutamate, D-serine, ATP, + K adenosine, GABA, TNFα Acon Presynapc 4 potenal AMPA-R neuron 2 Na+ Postsynapc Epilepform K+ 3 neuron discharge Synapc NMDA-R Na+ 1 vesicles 2+ Na+ Ca TRENDS in Neurosciences + + Figure 1. Schematic model depicting selected interactions between astrocytes and excitatory neurons. Voltage-gated Na and K channels (1) generate action potentials in the presynaptic neuron, leading to the exocytotic synaptic release of neurotransmitter glutamate (2). Glutamate activates AMPA and NMDA receptors (3) in the postsynaptic + 2+ membrane, causing excitatory synaptic potentials generated by influx of Na and Ca . 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 in + + + GABA production. K released from neurons by voltage-gated (outwardly rectifying) K channels enters astrocytes via inwardly rectifying K channels (Kir4.1) (7) and is 2+ distributed into capillaries. Aquaporin-4 (AQP4) concentrated at astrocytic endfoot processes regulates water balance (8). Ca waves (9) stimulate the release of gliotransmitters (10) that can influence neuronal excitability. The inhibitory substance adenosine is taken up into astrocytes by the equilibrative nucleoside transporters ENT1 and ENT2 and concentrative nucleoside transporter CNT2. Excessive adenosine kinase in reactive astrocytes increases the removal of adenosine (11), enhancing hyperexcitability. blood, thus regulating interstitial fluid osmolarity and ECS murine and human polymorphisms or mutations of + volume. Mice lacking AQP4 or components of the dystro- KCNJ10, which encodes the astroglial Kir4.1 K channel, phin-associated protein complex that anchors AQP4, in- are associated with epilepsy [21]. Because Kir4.1 dysfunc- + cluding a-syntrophin and dystrophin, have altered seizure tion can compromise K spatial buffering [22], both acquired susceptibility, and epilepsy can complicate human muscu- and genetic epilepsies could result from glial pathology. lar dystrophy affecting the dystrophin complex [10,14]. In Impaired Kir channel function in the CA1 region in MTS MTS specimens, AQP4 is redistributed from perivascular suggests that this pathological mechanism is clinically rele- glia endfeet to the perisynaptic space [15]. This may en- vant [23,24]. Impaired gap junction coupling between astro- + hance water entry into the neuropil but impair water cytes may also disrupt spatial K buffering, but this remains egress into the perivascular space, swelling astrocytes, controversial [6,21]. The homeostatic role of astrocytes contracting the ECS, and increasing excitability [6]. Thus, extends from ions and water balance to neurotransmitter glial AQP4 dysfunction can impair water delivery to the levels and maintaining BBB function. ECS, increasing susceptibility to seizure [16]. Glia provide an osmotically neutral spatial buffering Regulating neurotransmission + + system for K using inward rectifying K channels (Kir) Glutamate uptake by high-affinity membrane transporters + that carry K ions into cells accompanied by water entry is essential for maintaining low ambient levels of gluta- through AQP4 to maintain osmotic balance. Excessive mate. Uptake is of particular importance when there is + local concentrations of K predispose to seizures [17]; intense excitatory synaptic activity, as occurs during epi- impaired glial buffering may help cause epilepsy [18]. leptic discharges. Uptake mechanisms prevent spill-out of Conditional knockout of Kir4.1 depolarizes glial mem- transmitter from the synaptic cleft, thus regulating cross- branes, inhibits potassium and glutamate uptake, and talk between neighboring
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