Neurochemical alterations related to focal epilepsy

 

Maria da Graça Naffah Mazzacoratti

 Disciplinas de Bioquímica e Neurologia Experimental da UNIFESP, São Paulo, SP, Brazil

 

Resumo

Crises parciais, as principais características das epilepsias focais têm sido relacionadas a importantes impactos no cérebro, assim como com a eventual evolução dessas síndromes. Assim, diferentes autores têm demonstrado que crises de longa duração desencadeiam uma complexa alteração neuroquímica em neurônios e células da glia, principalmente na epilepsia do lobo temporal. Esses eventos imediatos ou de longa duração modificam  o ambiente através da alteração de fatores tróficos, enzimas, proteínas do citoesqueleto, proteínas da matrix extracelular e fosforilação de macromoléculas. Além disso, crises podem induzir proliferação de células da glia (gliose) e morte neuronal. Essas modificações promovem a remodelação sináptica que pode afetar a excitabilidade neuronal de estruturas temporais, levando ao aparecimento de uma hiperexcitabilidade permanente. Infelizmente, as epilepsias focais e em particular a epilepsia do lobo temporal não são disfunções simples. As alterações neuroquímicas encontradas no cérebro de animais, submetidos aos modelos experimentais de epilepsia ou em humanos mostram alto grau de complexidade, que serão sumarizadas abaixo. Devido a essa complexidade, focalizaremos apenas as alterações relativas à epilepsia do lobo temporal.

 

 

Abstract

Partial seizures, the main characteristic of focal epilepsies, have been related to important brain impact as well as to the eventual evolution of these syndromes. Thus, different authors have demonstrated that long-lasting seizures unchain a complex chemical cascade, triggering neurochemical alteration in neurons and glial cells mainly in temporal lobe epilepsy (TLE). These immediate or long-lasting events can modify the cellular environment through changes of ionic gradient across the cell membrane, alteration of gene expression such as receptors, trophic factors, enzymes, proteins from cytoskeleton, protein from matrix and the phosphorylation of macromolecules. Furthermore, seizures can induce reactive gliosis, generated by cell death, induced by these long-lasting convulsions.  These modifications promote synaptic remodeling, which can change the excitability of neurons from temporal structures, leading to the appearance of brain damage and a permanent hyper-excitability. Unfortunately, focal epilepsies, and in particular the temporal lobe epilepsy are not an easily understandable brain dysfunction.  The neurochemical alteration found in the brain of experimental animals as well as in human brain show high degree of complexity, which will be summarized below. Due to this high complexity we will focus only the alterations related to the temporal lobe epilepsy.

 

 

A. Neurotransmission

 

Since the hippocampal formation seems to bee an important structure in temporal lobe epilepsy several authors have reported neurochemical alterations in this structure.  The hippocampus of rats submitted to the epilepsy model induced by pilocarpine shows increased utilization rate of norepinephrine (NE) and decreased utilization rate of dopamine during the acute, silent and chronic period of this model.  As reported, the utilization rate of serotonin was increased only the acute phase (Cavalheiro et al., 1994).

The NE depletion has been associated to increased seizure susceptibility and NE release may be related to protection against seizure spread or initiation (MacIntyre and Edson, 1982). In contrast, in seizures induced by lithium plus pilocarpine, dopamine D2 antagonist  reduce the threshold for convulsion  and D1 antagonist prevent the convulsive activity, showing that dopaminergic receptors exert opposite function on the regulation of convulsive activity in this model (Barone et al., 1991) .

According to Radley and Jacobs (2003), pilocarpine-induced SE increases cell proliferation in the dentate gyrus of adult rats via 5HT_1A receptor-dependent mechanism, since the blockade of this receptor prevents the seizure-induced enhancement neurogenesis. However, this treatment did not blockade the development of mossy fiber sprouting neither the appearance of spontaneous seizures in the epilepsy model induced by pilocarpine. On the other hand, intra-hippocampal infusion of DA and 5HT via microdialysis probe, in determined concentration, protected the brain from seizures induced by pilocarpine (Clinckers et al., 2004). Taken together, these dada associate monoaminergic pathway with the development of temporal lobe epilepsy. 

 Concerning to aminoacidergic neurotransmission, the acute phase of pilocarpine model was characterized by an increased glutamate release, in the hippocampus (Cavalheiro et al., 1994, Costa et al, 2004). Hippocampal synaptosomes from animals presenting long-lasting SE (12 h) still showed increased release of glutamate. However, the uptake of this amino acid is normal in animals presenting 12h of SE, suggesting an excitatory phenomenon, during the acute phase of pilocarpine model. In addition, Ormandy et al (1989) have showed that MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist produces an effective and dose-dependent anticonvulsant action on lithium-pilocarpine model, suggesting that activation of NMDA receptor plays an important role in SE and brain damage. Using microdialysis probes Smolders et al (1997) described a long-lasting increase in the release of glutamate in the rat hippocampus, also supporting the excitatory phenomenon. Indeed, when glutamate activates NMDA receptors, the intracellular Ca⁺⁺ raises inducing activation of lipases, proteases and nucleases, killing the cell by necrosis and/or apoptosis.

The expression of proteins related to NMDA receptor is also modified in pilocarpine model of epilepsy.  Mint1 or X11 alpha plays an important role in vesicle synaptic transport toward the active zone at presynaptic site and also participates in the transport of NR2B subunit of NMDA receptor at the postsynaptic site. According to Scorza et al. (2003) this protein, mainly expressed in CA1 regions of control animals, presented its levels decreased 5 h after SE onset and increased levels during the silent and chronic groups, suggesting that this protein is related to plasticity during epileptogenesis. 

 In addition, Smolders et al (2004) reported anticonvulsant effects of metabotropic glutamate receptors (mGlu1 and mGlu5) antagonist in this model and other authors also showed increased expression of mGluR2/3 in stratum lacunosum moleculare of CA1 and dentate gyrus, one day after pilocarpine-induced SE. Funke et al., (2003) also found increased expression of mGluR1 in all hippocampal formation during the acute and silent periods, showing the participation of other glutamate receptors in excitatory phenomenon of temporal lobe epilepsy.   According to Khan et al. (1999) the anticonvulsant action of diazepam against pilocarpine-induced seizures is associated with a prompt attenuation of extracellular hippocampal glutamate overflow, without concurrent alteration of pilocarpine-induced increases in endogenous GABA levels. 

The silent phase of pilocarpine model is marked by an important unbalance between inhibition and excitation (Cavalheiro et al, 1994). The decreased concentration of GABA in the hippocampus, during the silent period, could suggest an increased release of this amino acid in attempt to control the tissue excitability. In contrast, the increased concentration of glutamate in the hippocampus could suggest a potential excitatory pathway of this structure, probably responsive for the appearance of spontaneous seizures.

According to Silva et al (2002), a diffuse decrease of parvalbumin, isoform 65 of glutamic acid decarboxylase (GAD65) and GABA transporter (GAT1) in the sensorimotor cortex pointed out to specific neocortical disturbance in GABAergic inhibition, which could play a crucial role in seizure generation and expression on pilocarpine-treated animals. In addition, alpha 5 subunit of GABA_A receptor is also capable of substantial and prolonged down regulation in pyramidal neurons from hippocampal formation of pilocarpine-treated animals (Houser et al., 2003).

Thus, according to several authors, the temporal lobe epilepsy has been related to excessive excitability in limbic structures, low function of inhibitory pathways or the association between both events (Meldrum, 1991).

 

B. Transduction signal

 

 As consequence of neurotransmission alteration, the transduction signal through plasma membrane is also modified, changing neuronal metabolism and genes expression.  Several studies have shown that short or long-lasting seizures can modify the expression of some genes, mainly the transcription factors such as c-fos and jun-B, c-Jun and Jun D, which are related to genome control.  The detection of c-fos, the immediate-early gene product, is thought to reflect at least in part, in acute metabolic activation of specific brain regions. In addition, increased expression of c-fos was found in the hippocampus of rats submitted to long-lasting seizures, induced by pilocarpine (Barone et al., 1993). According to Backer at al., (2003) high number of differentially expressed genes (dentate gyrus, 400 genes and CA1, 700 genes) was observed 3 days after SE induced by pilocarpine. The majority of these up regulated genes were associated with mechanisms of cellular stress and injury. Fourteen days after SE numerous transcription factors and genes linked to cytoskeletal and synaptic reorganization were differentially expressed and during the chronic phase genes involved in various neurotransmission pathways were found differentially expressed in the hippocampus of these animals.  In addition, Mudò et al (1996) showed increased expression of BDNF (brain-derived neurotrophic factor), NGF (neuronal growth factor) as well as their receptors in the dentate gyrus, 3 h after pilocarpine-induced SE. 

The activation of growth factors receptors induces the auto-phosphorylation of these receptors and activation of different kinase proteins, including the phosphorylation of proteins on tyrosine residues, which are important in cell cycle and intracellular signaling mechanisms.  These phosphotyrosine proteins (PTyP), of different molecular weight, have been found to be increased in the hippocampus of rats during the early stages of pilocarpine-induced SE (Funke et al., 1998), showing that several intracellular events could undergo modifications during long-lasting seizures, mainly in CA3 region. Carnevalli et al. (2004) also found extensive phosphorylation of alpha subunit of translation initiation factor 2 (eIF2 alpha) in mice submitted to SE induced by pilocarpine, showing that the synthesis of proteins is promptly modified in the hippocampus of these animals. 

Results emerged from intracerebral infusions of BDNF and from transgenic mice overexpressing BDNF showed enhanced response of these animals to epileptogenic stimuli (Croll et al., 1999). According to Poulsen et al., (2002) organotypic hippocampal slices exposed to 5mM pilocarpine for up to 7 days displayed increased BDNF expression, which is correlated with increased neuropeptide Y immunoreactivity, known to accompany seizure activity. Pilocarpine-treated animals also exhibited increased immunoreactivity against neuropeptide Y in regions of mossy fiber terminals, in the dentate gyrus inner molecular layer, entorhinal cortex, amygdala and sensorimotor areas (Lurton and Cavalheiro, 1997).

The increased expression of growth factors is also related to Mitogen Activated Protein Kinase (MAPK) activation. After binding an agonist, trk receptors phosphorylate themselves on cytoplasmic domains on tyrosine residues, which became docking sites for intracellular signaling proteins. Shc adaptor proteins associate themselves with specific site in trk receptors, activating a signaling pathway involving Ras, Raf , MAPK1, MAPK2, Mek 1 and Mek 2. As consequence, the transcription factors and the regulation of gene expression is modified.   As reported by Garrido et al. (1998) several limbic structures showed increased levels as well as increased phosphorylation of MAPKs (ERK1 and ERK2), which are important during the induction of the de novo synthesis of several proteins.  According to He et al. (2002) trk-B undergoes phosphorylation in the mossy fiber pathway and CA3 stratum oriens of the hippocampus during epileptogenesis. 

Others intracellular signaling pathways may also be modified during epileptogenesis. Levels of the neuromodulin or growth associated phosphoprotein, (B-50 or GAP-43), which is activated by PKC are modified in the hippocampus of rats in the pilocarpine epilepsy model.  GAP-43 has been related to processes underlying cell proliferation in fetal human brain and is correlated specifically with differentiation and outgrowth of axons. This protein showed its levels increased in the inner molecular layer of the dentate gyrus (regions associated with the mossy fiber sprouting), during the acute, silent and chronic period, in rats submitted to pilocarpine-induced epilepsy (Naffah Mazzacoratti et al., 1999). According to several authors the GAP-43 activation may be also induced by glutamate, acting on NMDA receptor, since the blockade of this receptor by MK801 prevent the GAP-43 expression as well as the mossy fiber sprouting (McNamara and Routtenberg, 1995). In addition, Tang at al (2004) has showed expression of different isoforms of PKC in the rat hippocampus after pilocarpine-induced SE, mainly in CA1 and dentate gyrus.

 

C. Inflammatory mediators in epileptogenesis

 

During long-lasting seizures the activation of inflammatory processes may occur. Reactive gliosis such as astrocytes and microglia appears as tardy form (Niquet et al., 1994). As reported by Garzillo and Mello (2002) 60 days (chronic phase) after pilocarpine-induced SE prominent astrocytes could still be seen in different brain areas.  The activated microglia has been blamed as the source of the main inflammatory cytokines. De Simoni et al., (2000) described increased expression of mRNA for IL-1β,  IL-6, iNOS and TNFα after seizures induced by electrical stimulation in the dorsal hippocampus. These factors remain increased 60 days after the insult.

The glial scar, generally epileptogenic, is able to produces trophic factors, which will support the axonal sprouting and other anatomic substrates for maintenance of hyperexcitability.

Another pathway, involved in the inflammatory processes, is linked to prostaglandin (PG) release. These eicosanoids are produced after action of phospholipase A2 on phospholipids, release of arachidonic acid, which could be done by action of glutamate on NMDA receptor (Pellerin and Wolf, 1991).  In addition, Naffah-Mazzacoratti et al (1995) showed increased release of prostaglandin PGF_2α during the acute phase, PGD₂ during the acute, silent and chronic period and PGE₂ only during the chronic phase of the epilepsy model induced by pilocarpine. According to Bazan (1989) in epileptic tissues occur backlog of these eicosanoids which are released by neuronal and glial cells, increasing the inflammatory processes. During PG formation, free radicals are produced, increasing the inflammatory process.

The free radicals are chemical entities produced during intermediary metabolism presenting an unpaired electron and for this reason show high reactivity. They are released during the mitochondrial transport chain, monoamines degradation, xanthine oxidase activity and by the metabolism of arachidonic acid.  When released in tissues are capable of inducing membrane damage and cell death. Thus, during SE induced by lithium plus pilocarpine occurs hyper-metabolism including increased glucose consumption, which results in abnormal respiratory chain and neuronal damage (Fernandes at al., 1999). 

Against free radicals the tissues present enzymes such as superoxide dismutase (SOD) and glutathione peroxidase, which are able to remove the superoxide anion (O₂^-) or H₂O₂, considered potent oxidant agents.  As reported by Bellissimo et al., (2001) rats presenting SE or spontaneous seizures showed decreased activity of SOD and increased levels of hydroperoxides (products lipid peroxidation) in the hippocampus of animals submitted to pilocarpine model of epilepsy. As the brain is more vulnerable than others tissues, the decreased activity of SOD could be related to cell death and brain damage, found in the hippocampus of these animals.

            Others compounds related to vessel dilatation, with consequence rupture of blood brain barrier, edema, pain and inflammatory processes are the kinins. These polypeptides are produced after proteolysis limited action of kallikreins on high and low molecular weight kininogens. These short-living peptides are rapidly degraded by kininases (Bhoola et al., 1992) originating active metabolites such as des-Arg⁹BK, des-Arg¹⁰Kallidin and inactive products. The receptors are denominated B1 and B2 and both are coupled to G protein.  As reported, B2 receptor presents high affinity for BK (bradykinin) or Lys-BK (kallidin) and low affinity for the active metabolites, des-Arg⁹BK and des-Arg¹⁰Kallidin. In contrast, B1 receptor presents high affinity for des-Arg⁹BK and des-Arg¹⁰Kallidin and less affinity for BK or Lys-BK (Regoli and Barabe, 1980). Kinin B1 receptor agonists led to inositol phosphate generation, promoting a transient rise in intracellular Ca^{2 +} levels, after phospholipase C activation. Furthermore, stimulation of kinin B1 and B2 receptors induce tissue edema and phospholipase A₂ activation, producing prostaglandins (Bhoola et al., 1992).  In addition, kinin B1 and B2 stimulation also activate MAPK (ERK1/ ERK2) in cell culture, resulting in AP-1 translocation, modifying the immediate early gene expression.

Usually, kinin B1 receptor is not expressed at a significant level under physiologic conditions in most tissues, but its expression is induced by injury or upon exposure in vivo or in vitro to pro-inflammatory mediators, such as lipopolysaccharide and cytokines. Moreover, Ni and colleagues (1998) showed several evidences that nuclear factor kB (NF-kB) is also involved in the dynamic regulation of human kinin B1 receptor gene expression, during inflammatory processes.

 In contrast, kinin B2 receptor is constitutively and widely expressed in all nervous system (Calixto et al., 2000) and has been found in the nucleus of neurons from hippocampus, hypothalamus and cortex. Nevertheless, the real function of this receptor in neuronal nucleus is still unknown.

Bregola et al. in 1999 showed that endogenous kinin B1 agonist Lys-des Arg⁹ BK increases the glutamate overflow in kindled rats slices (40-50%) and, to a smaller extent (20%) in slices of kainate-treated animals, supporting the idea that kinin B1 receptor may play a role in TLE excitotoxicity. The authors also suggest that the relationship between Lys-desArg⁹ BK and glutamate release is not a mere consequence of seizures, but it is associated with a condition of latent hyperexcitability, found in epileptic tissues. In addition, Ongali et al.(2003) showed a significant decline of kinin B2 receptor binding sites, accompanied by an impressive increase of kinin B1 receptor binding sites labeling in the brain of rats submitted to kindling model of epilepsy.

            Studying the distribution of kinin B1 and B2 receptors and the expression of mRNA by Real-Time PCR of these receptors during the development of the epilepsy model induced by pilocarpine Argañaraz et al (2004)b found increased kinin B1 and B2 mRNA levels during the acute, silent and chronic periods and changes in kinin B1 receptors distribution. In addition, the immunoreactivity against kinin B1 receptors was increased mainly during the silent period, where clusters of cells could be visualized suggestion a local inflammation.  The kinin B2 receptor immunoreactivity also showed augmentation but mainly during the acute and silent periods, supporting the hypothesis that both kinin receptors are related to temporal lobe epilepsy.

Trying to understand the role of kinin B1 and B2 receptors in the physiopathology of temporal lobe epilepsy we development the epilepsy model induced by pilocarpine in B1 and B2 knockout mice (B1KO and B2KO, respectively) and behavior parameters, cell death and mossy fiber sprouting were analyzed. B1KO mice showed increased latency for the first seizure, associated to a decreased frequency of spontaneous seizures (chronic phase), when compared with their wild control mice. In addition, B1KO mice showed less cell death in all hippocampal formation associated to a minor grade of mossy fiber sprouting, when compared with wild mice. Furthermore, B2KO mice presented minor duration of the silent period and an increased frequency of spontaneous seizures (chronic phase), when compared with wild mice.  B2KO and wild mice showed similar pattern of cell death in the hippocampus, which was very intense when compared with saline-treated animals (Argañaraz et al, 2005a). The mossy fiber sprouting was also increased in B2KO mice, when compared to wild mice and saline-treated animals. Taken together these data suggest a deleterious effect for B1 receptor and a protective effect for B2 receptor during the development of the temporal lobe epilepsy.

 

D. Activity of ATPases

 

Among the mechanisms involved in regulation the cytosolic calcium are the Ca⁺⁺ ATPases, whose function is to restore the normal level of this ion into the cell. These Ca⁺⁺ ATPases constitute a class of proteins that falls into two distinct groups, termed SERCAs and PMCA, depending on whether they are inserted in endoplasmatic reticulum or in plasma membrane. SERCAs sequester calcium to sarco/endoplasmatic reticulum and SERCA2b is found in several brain structures. PMCAs promote the extrusion of this ion from neural cell, through plasma membrane.  According to Funke et al (2003) in the hippocampus of rats, submitted to pilocarpine model of epilepsy, the expression of SERCA2b as well as the PMCA enzymes is increased after 1 h of status epilepticus showing an attempt to control the tissue excitability during the early stages of the insult. The PMCA remained increased until the silent period, returning to control levels during the chronic phase. In contrast, regions vulnerable to cell death such as CA1, CA3 and hilus presented decreased expression of SERCA2b until the silent period, showing a deficit in the mechanisms related to calcium removal.

The activity of the Na⁺K⁺ ATPase is also modified in the hippocampus of pilocarpine-treated animals. According to Fernandes et al., (1996) this enzyme has its activity reduced during the acute and silent period and increased activity during the chronic phase showing that the hippocampus of these animals also show an ionic imbalance, related to its maintained excitability.

 

E. Matrix components

 

Metalloproteases (MMPs) from matrix are proteolytic enzymes necessary to model the cell medium, recycling receptors and other type of extracellular proteins. They are released as pro-enzyme, have the ion zinc as cofactor and are inhibited endogenously by tissue inhibitors of metalloproteases (TIMPs). An imbalance between MMPs and TIMPs has been related to brain damage. According to several authors the activity of MMPs as well as the TIMPs are modified in the hippocampus of pilocarpine-treated animals, relating these proteins to plasticity after injury. Other matrix components are the glycosaminoglycans and proteoglycans which are also modified into the brain of epileptic animals (Naffah-Mazzacoratti., 1999). The receptor protein tyrosine phosphatase β (RPTPβ), a proteoglycan, which are related to sprouting of axons has been associated with mossy fiber sprouting (Perosa et al.; 2002). The RPTPβ, expressed only by astrocytes in control tissues has its synthesis increased in pyramidal neurons, in the hippocampus, during the acute and silent phases, showing that the SE may modify the gene expression in epileptic rats.

Analyzing all these results we can observe that an insult is able to modify several signaling pathways in central nervous system.

In summary, pilocarpine may act on M1 and M2 muscarinic receptors. Activating M2 the adenylate cyclase is inhibited decreasing the release of acetylcholine, decreasing the neuronal excitation (Smolders, 1997).  On the other hand, binding to M1, the pilocarpine activates the phospholipase C producing diacylglycerol (DG) and inositol triphosphate (IP3), resulting in alteration in Ca⁺⁺ and K⁺ current, increasing excitability of the brain (Segal et al; 1988). This increased excitability probable occurs due to decreased activity of ATPases in the hippocampus, which could not repolarize the plasma membrane; neither promotes the calcium extrusion (Fernandes et al., 1996; Funke et al., 2003). The high concentration of Ca⁺⁺ promotes the high release of glutamate, inducing the status epilepticus (SE) (Smolders et al., 1997; Klan et al., 1999). The glutamate, acting on AMPA/KA receptors allows the entrance of Na⁺ and Ca⁺⁺ into the cell and, as consequence, the Mg⁺⁺, which blockade the NMDA receptor, is removed inducing the activation of this receptor by glutamate, allowing the entrance of more Ca⁺⁺ into the postsynaptic cell , which will induce excitotoxicity and cell death.

The tissue excitability and/or SE increase the utilization rate of noradrenaline (NA) and serotonin (5HT) with concomitant decrease in the utilization rate of dopamine (DA) (Cavalheiro et al., 1994). After docking to its own receptors these monoamines are degraded by MAO and COMT and during these processes free radicals can be formed.  These free radicals are also freed during glucose metabolism and mitochondrial transport chain, which is over activated during SE.  In addition, the superoxide dismutase (SOD) presented decreased activity during seizures, associated to an increased level of hydroperoxide in the hippocampus of epileptic animals (Bellissimo et al., 2001) showing tissue damage and lipid peroxidation.  

Glutamate on NMDA receptors promotes increased expression of GAP-43, which is linked to mossy fiber sprouting and hippocampal plasticity (McNamara et al., 1995, Naffah Mazzacoratti et al., 1999).

During the SE the expression of trophic factors such as NGF, BDNF and FGF (Mùdo et al., 1996) increase in the hippocampus, propitiating MAPK and PTyP activation (Garrido et al., 1998; Funke et al., 1998) inducing modification in genes expression. MAPK also may have protector action  or can be related to apoptosis process.

The trophic factor receptors are also associated to proteoglycans (PGs), from extracellular matrix. These proteoglycans (PG) some times may function as co-receptors for neurotrophins (Ruoslahti and Yamaguchi, 1991). In this context, the increased synthesis of chondroitim sulphate and RPTPβ (Naffah Mazzacoratti et al., 1999), found in the hippocampus of epileptic animals can be related to neurite outgrowth and/or mossy fiber sprouting (Fernaud-Espinosa et al 1994; Peles et al., 1998).  In addition, the RPTPβ also present phosphatase activity, removing the phosphate group from tyrosine residues in PTyP, modified during SE (Funke et al., 1998).        

The SE or the excess of glutamate in tissue can activate routes that culminate in kinins release and these polypeptides may act on kinin B1 and B2 receptors, which are over expressed in the hippocampus of epileptic animals (Argañaraz et al., 2004). The kinin B2 receptor has a protector role during epileptogenesis, while B1 is deleterious (Argañaraz et al., 2004).  Bradykinin (BK) as well as monoamines also induces prostaglandins (PG) release (Bazan et al., 1996). As reported by Naffah Mazzacoratti et al. (1995) the levels of PGE₂, PGD₂ and PGF2α is increased in the hippocampus of epileptic rats. During the PG synthesis also occur free radical production, which could be visualized by SOD and HPx analyses (Bellissimo et al., 2001).

BK also stimulates the MAPK pathway and binds to neurotrophins receptors (Fleming and Busse, 1997), perhaps mediating the phosphorylation of proteins on tyrosine residue (PTyP), changing the gene expression, contributing to plasticity found in the epileptic phenomena.

 

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