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Keywords:

  • Peroxynitrite;
  • Ictal events;
  • Glia;
  • Adenosine;
  • Gap junctions;
  • K+ buffering;
  • Kir channels

Summary

  1. Top of page
  2. Summary
  3. Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function
  4. Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy
  5. Spatial K+ Buffering in Epilepsy
  6. Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability
  7. Alterations of the Neurovascular Unit in Epilepsy
  8. Conclusion
  9. Acknowledgment
  10. Disclosure
  11. References

Astrocytes are increasingly recognized as equal partners to neurons, also contributing to neurologic disorders such as epilepsy. Activated astrocytes are a common hallmark in patients with mesial temporal lobe epilepsy and Ammon′s horn sclerosis. Blood–brain barrier (BBB) opening during status epilepticus has short-term proepileptic effects, as the ionic composition of serum interferes with neuronal excitability. In the long run, astrocytic uptake of albumin induces transforming growth factor β (TGFβ)–mediated signaling cascades, leading to changes in astrocytic properties. Down-regulation of astrocytic inward rectifier K+ channels and altered surface expression of the water channel, aquaporin 4 results in disturbances in spatial K+ buffering, thereby rendering the tissue more seizure prone. The expression of astrocytic gap junctional proteins connexin 43 (Cx43) and connexin 30 (Cx30) is altered in epilepsy, and changes in gap junctional communication were found in sclerotic hippocampal tissue in animal models of epilepsy. Although gap junctional communication might exert both proepileptic and antiepileptic effects, double knock out of Cx43 and Cx30 resulted in occurrence of spontaneous epileptiform events. Seizures are associated with massive increases in cerebral blood flow in order to cover the increased energy demand. Hemodynamic responses at the microcirculation level are mediated by astrocyte–pericyte interactions, sharing common mechanisms with spatial K+ buffering. Although many of the astrocytic mechanisms involving spatial K+ buffering, nitric oxide, adenosine, and metabotropic glutamate receptor (mGluR)-mediated signalling are altered in epilepsy, little is known how these alterations affect neurovascular coupling. In conclusion, astrocytic activation preceding alterations in neuronal function might critically contribute to epileptogenesis. Therefore, astrocytes represent a promising new target for the development of antiepileptic drugs.

Temporal lobe epilepsy is frequently associated with activation of astrocytes, indicated usually as an increased expression of glial fibrillar acidic protein (GFAP). Activated astrocytes display altered functional properties in human sclerotic tissue (Hinterkeuser et al., 2000; Seifert et al., 2004). The picture is complicated because these changes might be either proepileptic and contribute to the pathogenesis or they can represent an adaptive response of the tissue to cope with pathologic conditions. Opening of the blood–brain barrier (BBB) might be critically involved in astrocyte activation through albumin-mediated transforming growth factor β (TGFß)–dependent signaling (Ivens et al., 2007; Cacheaux et al., 2009). Down-regulation of gap junctional proteins, inwardly rectifying K+ channels (Kir.4.1), the glial excitatory amino acid transporters (EAAT1 and EAAT2), and dislocation of aquaporins (AQP4) were early signs of astrocyte activation induced by BBB disruption, as well as by focal application of albumin or TGFß. On the other hand, blocking TGFß-mediated signaling prevented development of hyperexcitability. These findings suggest that activation of astrocytes is a critical step in epileptogenesis preceding alterations in neuronal function (David et al., 2009).

Epileptic activity represents a massive metabolic burden to neurons and glia to restore ion gradients. To support energy metabolism, cerebral blood flow has to be increased in the seizure focus. Astrocytes play an important role in translation of neuronal activity into blood flow response in healthy tissue. Although many of those signaling cascades are altered in activated astrocytes, very little is known about neurovascular coupling in epilepsy. In the following we review recent findings on alterations of astrocytic function such as K+ buffering and transmitter metabolism in chronic epileptic tissue, as well as on the possible impact of these alterations on neurovascular coupling.

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[   Potentially proepileptic alterations of functional properties of activated astrocytes in epileptic tissue. Spatial K+ buffering in astrocytes requires the targeted surface expression of inwardly rectifying K+ channels (Kir4.1), the water channel aquaporin 4 (AQP4), and the gap junctional proteins connexin 43 and connexin 30. Down-regulation of Kir4.1, loss of AQP4 at the astrocyte end-feet, as well as alterations in gap junctional communication result in altered water and K+ homeostasis and enhanced neuronal excitability. On the other hand K+-dependent mechanisms of neurovascular coupling also become impaired. Disturbances in astrocytic gap junctional coupling will affect the trafficking of metabolic substrates, thereby exacerbating the effects of seizures on energy metabolism and neuronal survival. Decreased expression of glutamate transporters and glutamine synthetase might underlie increased ambient glutamate levels and decreased efficacy of inhibitory neurotransmission. Seizures are associated with enhanced formation of nitric oxide (NO) and reactive oxygen species (ROS). In addition to the deleterious effects of ROS on mitochondrial protein complexes and DNA, it also reacts with NO forming peroxynitrite (ONOO) at the vascular compartment. Oxidative–nitrosative stress impairs vasodilatory signaling by disturbing the balance of vasodilatory (PGE2) and vasoconstrictory 20-hydroxyeicosatetraenoic acid (20-HETE) arachidonic acid (AA) derivatives at the microvasculature. Furthermore, astrocytic catabolism of adenosine is enhanced, leading to decreased efficacy of adenosine-mediated functions such as suppression of neurotransmission and enhancement of vasodilation. ]

Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function

  1. Top of page
  2. Summary
  3. Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function
  4. Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy
  5. Spatial K+ Buffering in Epilepsy
  6. Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability
  7. Alterations of the Neurovascular Unit in Epilepsy
  8. Conclusion
  9. Acknowledgment
  10. Disclosure
  11. References

Pathologic alterations in the tightness of the BBB might range from changes in transbarrier transport, to transmigration of immune cells after local damage, to loss of tightness of tight junctions (Abbott et al., 2010). The latter is a hallmark of status epilepticus, trauma, inflammation, and hypoxia, leading to equilibration of serum electrolytes with the cerebrospinal fluid (CSF). This results in increased interstitial [K+] and likely lowered extracellular [Ca2+] ([Ca2+]o) and [Mg2+]o (Ivens et al., 2007). Decreases in divalent cation concentration facilitate neuronal excitability by reduced surface charge screening and activation of N-methyl-d-aspartate (NMDA) receptors, leading to augmented transmitter release (Mody et al., 1987). Further [Ca2+]o decrease during excessive neuronal activity may activate a transient receptor potential (TRP) channel–mediated unspecific cation current leading to subsequent neuronal depolarization (Hablitz et al., 1986). These effects are supported by the increases in [K+]o, which affects neuronal excitability by different mechanisms and may reduce the threshold for induction of seizures in a vicious cycle (Leschinger et al., 1993).

Astrocytic depolarization due to the rise in [K+]o lowers the capacity of these cells to transport glutamate, γ-aminobutyric acid (GABA), and glucose, as the driving force for these transport processes will be reduced. In the long run this will affect transmitter metabolism, detoxification of NH3, and the synthesis of the antioxidant glutathione (Papageorgiou et al., 2011).

In addition to the ionic changes following BBB opening, exudation of serum proteins will increase the colloidal osmotic pressure in the interstitial space resulting in an increased intracranial pressure. This might reduce local blood flow, particularly through small vessels. The resulting decline in oxygen and glucose supply will eventually lead to cytotoxic edema, causing a vicious cycle with expansion of BBB disruption.

Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy

  1. Top of page
  2. Summary
  3. Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function
  4. Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy
  5. Spatial K+ Buffering in Epilepsy
  6. Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability
  7. Alterations of the Neurovascular Unit in Epilepsy
  8. Conclusion
  9. Acknowledgment
  10. Disclosure
  11. References

The major gap junction proteins expressed by astrocytes are Cx30 and Cx43. Tracer spread studies performed on Cx30- and Cx43-deficient mice indicated that coupling of astrocytes is absent when both of these connexins are missing (Wallraff et al., 2006). Dye coupling in the hippocampus may predominantly depend on Cx43 (Gosejacob et al., 2011), the connexin that is down-regulated after opening of the BBB (Cacheaux et al., 2009).

Studies on connexin expression in animal models of epilepsy led to inconsistent results, with some providing support for increased mRNA and/or protein levels of Cx43 and Cx30, while others reporting no changes, or decreased Cx43 levels (Steinhäuser et al., 2012). This inconsistency may result from species differences, different animal models, and brain regions investigated as well as from differences in seizure duration and time points after induction of epilepsy.

Using biocytin diffusion, Xu et al. (2009) reported decreased interastrocytic coupling in the hippocampal CA1 region in a genetic mouse model of tuberous sclerosis, which is commonly associated with medically intractable seizures. In contrast Takahashi et al. (2010) observed increased coupling of hippocampal astrocytes in the systemic rat kainate model of epilepsy. Increased coupling has also been found in cultured astrocytes from human epileptic tissue specimens (Lee et al., 1995). Of course, culture condition may have influenced the functional phenotype of these astrocytes.

In human epileptic tissue, unchanged (Elisevich et al., 1997) or elevated (Naus et al., 1991; Collignon et al., 2006) Cx43 mRNA and/or protein levels have been reported. Conclusions from the human studies should, however, be drawn carefully because epilepsy is not a homogeneous condition, tissue is only available from the chronic state of the condition, and treatment of patients with antiepileptic drugs might differently affect connexin expression. In addition, tumor or autopsy specimens were used as “controls,” and it cannot be ruled out that the apparent changes in connexin levels might have actually been caused by changed expression in this “control” tissue (Nemani & Binder, 2005). Furthermore, alterations in mRNA or protein levels do not necessarily correlate with changes in functional coupling. Functional assays are therefore inevitable for reliably investigating the role of astrocyte gap junctions in human epilepsy.

Spatial K+ Buffering in Epilepsy

  1. Top of page
  2. Summary
  3. Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function
  4. Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy
  5. Spatial K+ Buffering in Epilepsy
  6. Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability
  7. Alterations of the Neurovascular Unit in Epilepsy
  8. Conclusion
  9. Acknowledgment
  10. Disclosure
  11. References

Astrocytes in the sclerotic hippocampus of patients with temporal lobe epilepsy express unusual immunohistochemical and functional phenotypes, including altered gap junction coupling, decreased expression of Kir 4.1, the major type of astrocytic inward rectifier K+ channel (Steinhäuser et al., 2012), as well as disorganization of AQP4 surface distribution (Kim et al., 2010). These changes affect spatial K+ buffering, which is critical to control neuronal excitability (Gabriel et al., 1998; Wallraff et al., 2006). In healthy tissue, activity dependent [K+]o accumulation leads to depolarization of astrocytes (expressing high levels of glutamate transporters and gap junctions), that form an electrical and metabolic syncytium. Depolarization will spread within the astrocytic syncytium, leading to subnernstian depolarization, driving therefore net K+ uptake at sites of maximal K+ accumulation and facilitated K+ release at astrocytic end-feet (Dietzel & Heinemann, 1983). This process is associated with the generation of slow field potentials, to an extent that might affect neuronal excitability through ephaptic interactions and K+ accumulation (Konnerth et al., 1984). AQP4 is localized in proximity to Kir4.1 channels at the glial end-feet, suggesting that K+ buffering is associated with directed water movements (Dietzel & Heinemann, 1983; Kofuji & Connors, 2003). Down-regulation of Kir4.1 channels is frequently seen in tissue samples from patients with temporal lobe epilepsy as well as in in vivo models of epilepsy (Hinterkeuser et al., 2000). Alterations in spatial K+ buffering can be investigated by studying effects of the Kir channel blocker Ba2+ on stimulus induced or iontophoretically applied [K+]o elevations. Application of Ba2+ was no more able to augment stimulus-induced [K+]o transients in tissue from chronic epileptic animals as well as in slices from sclerotic human hippocampus (Gabriel et al., 1998). Impaired K+ buffering led to [K+]o accumulation, even during low frequency stimulation, and it provoked epileptiform discharges (David et al., 2009).

Alterations in Kir4.1, and AQP4 expression and consequent impairment of K+ buffering is sufficient to induce epileptic activity, as genetic down-regulation of astrocytic Kir4.1 led to an epileptic phenotype, whereas prolonged seizure duration was observed in AQP4 (−/−) mice (Binder & Steinhäuser, 2006; Djukic et al., 2007). However, another study suggested that astroglial AQP4 channels are specifically required for proper K+ buffering under physiologic condition, and demonstrated enhanced gap junction coupling and [K+]o redistribution in AQP4 deficient mice (Strohschein et al., 2011).

Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability

  1. Top of page
  2. Summary
  3. Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function
  4. Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy
  5. Spatial K+ Buffering in Epilepsy
  6. Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability
  7. Alterations of the Neurovascular Unit in Epilepsy
  8. Conclusion
  9. Acknowledgment
  10. Disclosure
  11. References

The role of interastrocytic gap junction communication in the pathophysiology of epilepsy is still elusive. According to the concept of spatial K+ buffering, impaired gap junction coupling results in insufficient [K+]o clearance and epileptiform activity. Indeed, antidromic stimulation in hippocampal slices with coupling-deficient astrocytes (Cx30−/− Cx43flox/flox hGFAP-Cre mice; dko mice) led to increased K+ accumulation, and the dko mice showed a reduced threshold for the generation of epileptic activity and presented with spontaneous hyperactivity (Wallraff et al., 2006). However, a potential proepileptic function of astroglial networks was also proposed (Rouach et al., 2008). These authors demonstrated that gap junctions mediate trafficking of energetic metabolites from blood vessels to the site of high energy demand in an activity-dependent manner, and they suggested that this process might be important to sustain glutamatergic synaptic activity under pathologic conditions. A second possible seizure-promoting function of the astroglial syncytium may arise from its contribution to the propagation of intercellular Ca2+ waves, which have been shown to mediate nonsynaptic neuronal synchronization via glutamate release (Angulo et al., 2004; Fellin et al., 2004). Increased astrocytic coupling may facilitate the propagation of Ca2+ waves, leading to hypersynchronization and spread of ictal activity (Gómez-Gonzalo et al., 2010). Therefore, reduction of astrocytic coupling would on the one hand provoke neuronal hyperexcitability, due to impaired K+ and glutamate clearance but, on the other hand, might have anticonvulsant consequences as hyperactivity could not be fueled, due to insufficient supply of energetic metabolites. In addition, decreased coupling would hamper the spread of Ca2+ waves and therefore attenuate synchronization of neuronal activity.

Pharmacologic inhibition of gap junction communication by gap junction blockers as well as by substances producing intracellular acidification was reported to be anticonvulsive, whereas alkalinization-induced potentiation of gap junction communication enhanced epileptiform activity (Steinhäuser et al., 2012). However, most gap junction blockers are not specific and do not discriminate between connexin isoforms and thus cell types. It remains mostly unclear whether the effects of the blockers were caused by inhibition of gap junctions between neurons or glial cells. The situation is further complicated by the fact that both pharmacologic blockade and genetic ablation of connexins may not only inhibit intercellular gap junctions but also connexin hemichannels, which might differently affect excitability.

Alterations of the Neurovascular Unit in Epilepsy

  1. Top of page
  2. Summary
  3. Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function
  4. Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy
  5. Spatial K+ Buffering in Epilepsy
  6. Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability
  7. Alterations of the Neurovascular Unit in Epilepsy
  8. Conclusion
  9. Acknowledgment
  10. Disclosure
  11. References

Seizures represent a massive metabolic burden, and cerebral blood flow has to be increased accordingly to deliver substrates into metabolically active areas. An increase in cerebral blood flow was observed in the seizure focus, whereas a decrease could be observed in neighboring areas (Zhao et al., 2011). Such hemodynamic anomalies in combination with electroencephalography (EEG) recording can be effectively used to locate seizure foci in presurgical evaluation (Schwartz, 2007). There is a longstanding debate over whether increased blood flow is sufficient to meet the enormous metabolic demand of epileptic activity. During seizures, tissue lactate levels are increased, whereas levels of phosphocreatine, glucose, glycogen, and often ATP decrease (Folbergrová et al., 2000). Neuronal activity results in adaptive changes in energy metabolism called neurometabolic coupling (Kann & Kovács, 2007). As a byproduct of enhanced energy metabolism, oxygen-centered free radicals are formed, leading to oxidative damage of mitochondrial enzymes and DNA (Kovács et al., 2002; Kudin et al., 2009). Oxidative stress–induced metabolic dysfunction might be responsible for the interictal hypometabolism of epileptic foci and contribute to progression of certain epilepsies (Kann et al., 2005; Kann & Kovács, 2007). Excessive formation of another free radical, nitric oxide (NO), during seizures was revealed both in vivo and in vitro (Kato et al., 2005; Kovács et al., 2009). Physiologic NO formation is involved in the regulation of blood flow, either depending on neuronal activity (de Vasconcelos et al., 2005) or as a permissive factor by inhibiting synthesis of vasoconstrictory 20-hydroxyeicosatetraenoic acid (20-HETE) in arteriolar smooth muscle (Gordon et al., 2008; Attwell et al., 2010). Besides neurons, pericytes might be a major producer and first victim of reactive oxygen species (ROS). Pericytic ROS formation is involved in contractile responses upon shear stress and angiotensin II signaling (Ungvari et al., 2006; Kovács et al., 2011). However, NO overproduction during seizures in the presence of ROS results in oxidative-nitrosative stress of pericytes likely leading to disturbances of neurovascular coupling analog to the situation found in stroke, hypertension, and Alzheimer’s disease (Iadecola et al., 2009; Yemisci et al., 2009). This might explain pericyte damage and alterations of the neurovascular unit found in epileptogenic areas (Liwnicz et al., 1990).

Functional hyperemia was described >100 years ago, and by now numerous processes and substrates have been shown to be involved in the regulation of cerebral blood flow (Attwell et al., 2010). In addition to the direct neuronal effects on vasculature exerted by catecholamines, acetylcholine, neuropeptides, or NO, astrocytes are critically involved in regulation of hemodynamic responses (Gordon et al., 2008; Filosa, 2010). Astrocytic processes ensheathe both the synapses and the abluminal surface of vessels. Moreover, astrocytes are equipped with neurotransmitter receptors and transporters and they can release vasoactive substances such as NO, arachidonic acid derivatives, adenosine, and ATP. Recently astrocyte–pericyte interactions were identified as determinants of functional hyperemia at the microcirculation level (Peppiatt et al., 2006). Other than their role in neurovascular coupling, pericytes are involved in angiogenesis: they regulate the tightness of the BBB and are responsible for the polarized expression of molecules involved in spatial K+ buffering (Abbott et al., 2010; Armulik et al., 2010). Consequently, disturbed pericyte–astrocyte interactions in epileptic tissue might underlie the deregulation of AQP4 surface expression and contribute to abnormal angiogenesis (Liwnicz et al., 1990; Armulik et al., 2010; Morin-Brureau et al., 2011). Activated astrocytes might also induce vascular remodeling by alteration of thrombospondin signaling and regulation of the activity of matrix metalloproteases (Risher & Eroglu, 2012).

In addition to its effect on tissue excitability, spatial K+ buffering might also contribute to the coupling of neuronal activity to blood flow responses (Attwell et al., 2010; Filosa, 2010). Moderate rises in [K+]o due to K+ release from glial end-feet covering the abluminal surface of vessels might lead to vasodilation by increasing the conductance of Kir2.1 channels in smooth muscle cells. One possible source of K+ elevation would be a release via Kir4.1 channels involved in spatial K+ buffering. However, in chronic epileptic tissue, the most critical components are either missing (down-regulation of Kir4.1 channels at the astrocytic end-feet) or their localization is disturbed (AQP4), suggesting limited influence of this mechanism. An alternative source of K+ elevation involves activation of astrocytic metabotropic glutamate receptors (mGluRs) leading to rise in [Ca2+]i and subsequent activation of large conductance Ca2+-activated K+ (BK) channels (Attwell et al., 2010; Filosa, 2010). In addition, mGluR activation might induce release of vasodilatory arachidonic acid derivatives, and this effect might be even enhanced due to increased extracellular lactate levels during seizures (Gordon et al., 2008). Moreover, astrocytes express K2P K+ channels, which might contribute to glial K+ release (Seifert et al., 2009).

These mechanisms were found to be functional also in in vitro models of epilepsy. Ictal and to a minor extent also interictal discharges, evoked both a Ca2+ increase in astrocyte end-feet and a vasomotor response (Gómez-Gonzalo et al., 2011). However, these studies were carried out in healthy tissue, and could not take into account the effects of up-regulation of astrocytic mGluRs, down-regulation of astrocytic glutamate transporters, and the elevated interstitial glutamate level present in chronic epileptic tissue (Steinhäuser et al., 2012). Indeed, hemodynamic responses to hypoxia and vasodilators are decreased following seizures, indicating deregulation of the mechanism underlying neurovascular coupling (Parfenova et al., 2005).

Another important regulator of vessel diameter is the “metabolic messenger” adenosine, formed by ectonucleotidases from ATP of glial or neuronal origin. Besides its inhibitory effect on synaptic transmission, adenosine also contributes to functional hyperemia. Blocking adenosine receptors reduces blood flow increases during kainic acid–induced seizures (Pinard et al., 1990). In chronic epileptic tissue, adenosine concentration is decreased due to up-regulation of adenosine kinase that metabolizes adenosine into 5-AMP, eliminating its effect on the vasculature (Boison, 2010). Consequently, excitability will increase, whereas neurovascular coupling becomes impaired in chronic epileptic tissue.

Conclusion

  1. Top of page
  2. Summary
  3. Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function
  4. Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy
  5. Spatial K+ Buffering in Epilepsy
  6. Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability
  7. Alterations of the Neurovascular Unit in Epilepsy
  8. Conclusion
  9. Acknowledgment
  10. Disclosure
  11. References

Given that about 30% of patients with epilepsy have poor seizure control by the currently available antiepileptic drugs, there is an increasing demand for novel therapeutic targets in epilepsy. Our understanding of altered functional properties of activated astrocytes largely increased during the last decade due to application of advanced electrophysiologic and imaging techniques. However, there are many open questions concerning how these changes contribute to the pathogenesis of epilepsy. At present the most promising mechanisms to interfere with appear to be the astrocytic regulation of (1) ion and water homeostasis, (2) the hemodynamic responses, and (3) the metabolism of neurotransmitters. In addition, new targets might emerge by discovering the role of activated astrocytes in regulation of synapse formation (Dityatev & Rusakov, 2011; Allen et al., 2012; Risher & Eroglu, 2012; Wang et al., 2012).

References

  1. Top of page
  2. Summary
  3. Acute Consequences of BBB Opening on Neuronal Excitability and Astrocytic Function
  4. Alteration of Connexin Expression and Gap Junctional Communication in Epilepsy
  5. Spatial K+ Buffering in Epilepsy
  6. Impact of Astrocyte Coupling on Homeostasis, Nutrient Supply, and Neuronal Excitability
  7. Alterations of the Neurovascular Unit in Epilepsy
  8. Conclusion
  9. Acknowledgment
  10. Disclosure
  11. References
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