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Neuronal migration, apoptosis and bipolar disorder
Migración neuronal, apoptosis y trastorno bipolar
Ezequiel Uribea,b,
Corresponding author
ezequiel.uribe@hotmail.com

Corresponding author.
, Richard Wixa,b
a Universidad de Carabobo, Escuela de Medicina, Departamento de Fisiología, Laboratorio de Neurofisiología, Valencia, Venezuela
b Hospital Psiquiátrico Dr. José Ortega Duran, Campo Universitario de Barbula, Valencia, Venezuela
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Bipolar disorder is currently considered a neurodevelopmental disease<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> that involves a considerable loss of quality of life and cognitive faculties in the intermediate term&#46; The theories that back this hypothesis represent the best approximations in the search for the molecular origins of psychiatric disorders&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> after having identified alterations in the expression of different genes that provoke the migration of GABAergic interneurons from their site of origin to their final location in specific cortical circuits&#46; In bipolar disorder&#44; there is a 27&#37; deficit of interneurons in the cerebral cortex<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and hippocampus&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> There is also a high expression of pro-apoptotic genes<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> such as Bcl-2-associated x protein &#40;BAX&#41;&#44; Bcl-2-associated death promoter &#40;BAD&#41;&#44; caspase-9 and caspase-3&#44; along with a decrease in the expression of anti-apoptotic genes such as brain derived neurotrophic factor &#40;BDNF&#41; and B-cell lymphoma 2 &#40;Bcl-2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> When the interneurons migrate&#44; they require the signalling of extracellular molecules that synergically mediate their transfer and posterior incorporation to specific neuronal circuits&#46; The protomap hypothesis formulates that a neuron&#44; from its birth&#44; has defined genetic instructions as to the exact place of migration and synaptic connections that it will establish when it incorporates into functional circuits&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> so that if it incorporates itself erratically to these circuits&#44; it will establish abnormal synaptic connections that will lead to its death&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> Neuronal death represents a phenomenon needed in the central nervous system&#44; which determines the exact number of cells that will constitute specific neuronal circuits&#46; In spite of the fact that neuronal death is present throughout a normal subject&#39;s life&#44; it is much more intense during neurodevelopment because of the high rate of neurogenesis in this period&#46; There are at least 3 types of neuronal death known&#58; apoptosis&#44; autophagy and necrosis&#46; With respect to mental disease and the presence of neuronal death in it&#44; we enter into an intense debate in which the uncertainty of isolated and reductionist research&#44; lacking an overall vision&#44; prevail&#46; Some investigators have recently identified the activation of pro-apoptotic elements such as caspase-3 in some neuronal forms after the abolition of synaptic connections by axotomy<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#59; this makes apoptosis the most attractive form of neuronal death when justifying the deficit of interneurons in the cerebral cortex of the subject with bipolar disorder&#46; At any rate&#44; in their migration process&#44; interneurons require the action of molecules that stimulate cell survival&#44; molecules with an alteration in their expression that confers a risk of having the disorder &#40;see further on&#41;&#46; In this review article&#44; we present the analysis of 3 of the elements involved in bipolar disorder&#58; BDNF&#44; Neuregulin 1 &#40;Nrg1&#41; and Reelin&#46; We also cover the pro-apoptotic pathways that trigger their abnormal expression&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Migration of GABAergic interneurons and bipolar disorder</span><p id="par0010" class="elsevierStylePara elsevierViewall">The migration of GABAergic interneurons is a complex process mediated by the expression of hundreds of genes synergically&#44; with a fine control that guarantees not only correct migration&#44; but also complete maturation in the search for achieving appropriate inclusion in a specific inhibitory circuit &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; BDNF plays an essential role in the way GABAergic interneurons &#40;molecules deficient in bipolar disorder&#41; migrate to the cortex during neurodevelopment&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In rodents lacking expression of the BDNF receptor&#44; tropomyosin-related kinase B &#40;TrkB&#41;&#44; tangential migration is reduced in the embryonic period&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> BDNF production is subject to the expression of molecules of a synaptic nature&#44; such as calcium-dependent activator protein for secretion 2 &#40;CAPS2&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> in such a way that the greater the number of efficient synaptic connections established&#44; the greater the production of CAPS32 and&#44; consequently&#44; of BDNF&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Once tangential migration to the cerebral cortex has occurred&#44; interneurons require extracellular molecule signalling to migrate radially&#46; Reelin is a glycoprotein secreted by the Cajal-Retzius cells that links to specific receptors in the interneuron membrane to provoke radial migration&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Studies on rodents lacking expression of the gene for Reelin demonstrate its importance in the laminar configuration of the cerebral cortex&#46; The youngest neurons usually detain their migratory process in the deepest layers&#44; while adult neurons do so in the superficial layers&#46; This process is inverted in zero expression models for Reelin&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Consequently&#44; despite not affecting radial and tangential migration directly&#44; the interneurons reach an incorrect place due to the cortical layers being&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#8211;22</span></a> Some variations of the Reelin gene have been identified as a risk factor for developing bipolar disorder in females&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and a decrease in its expression would involve the same result in both sexes&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In addition&#44; some antidepressants and antipsychotics &#40;drugs commonly used in bipolar disorder&#41; increase Reelin expression in the prefrontal cortex&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> A direct relationship between alterations in Reelin gene expression and the deficit in glutamic acid decarboxylase &#40;GAD&#41; positive interneurons<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> has recently been identified&#59; patients with bipolar disorder had up to a 40&#37; deficit&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Nrg1 comprises a family of extracellular growth factors that require the expression of their receptor ErbB on the surface of the interneuron cell membrane during migration&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> activating a wide range of second messengers that culminate in the activation of transcription factors in the neuron nucleus&#46; Some polymorphic variations of Nrg1 predispose to the appearance bipolar disorder with its psychotic symptoms<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> and reduced migration of interneurons to the cerebral cortex was found in studies on rodents with the mutation for this gene&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Neuronal apoptosis and abnormal integration into synaptic circuits</span><p id="par0015" class="elsevierStylePara elsevierViewall">After the migratory process&#44; the GABAergic interneurons should integrate in neuronal circuits to carry out a specific role&#46; The molecular processes that mediate migration also stimulate interneuron maturation and there is a deficit of some of these molecules in the brain of a subject with bipolar disorder&#46; Consequently&#44; when they join that circuit&#44; they lack the differentiation needed to establish functional synaptic connections&#46; In any case&#44; whether the interneurons reach the improper place or they reach the correct place and establish aberrant synaptic connections&#44; they must be eliminated from the brain as they develop&#44; as part of a normal synaptic refinement process &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46; The prefrontal cortex in the patient with bipolar disorder presents a high expression of pro-apoptotic molecules such as BAD&#44; BAX&#44; caspase-3 and -9 and reduced expression of anti-apoptotic molecules such as Bcl-2&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> We consequently propose apoptosis as the model of cell death during the neurodevelopment of the bipolar subject&#44; justifying in this way the interneuron deficit existing in these patients&#46; Apoptosis is triggered through 2 pathways&#46; The first is the extrinsic&#44; which is activated by ligands of the tumour necrosis factor family that&#44; upon linking to its receptor in the neuronal surface&#44; promotes caspase-8 activation&#59; this in turn successively activates caspase-3&#44; -6 or -7&#44; finally inducing apoptosis&#46; The 2nd pathway is the intrinsic or mitochondrial&#59; when various molecules in the mitochondrial intermembrane space leave for the neuronal cytoplasm&#44; it is activated&#46; The main one of these molecules is Cytochrome C&#44; which forms a complex with Apaf-1 and dATP nucleosome designated apoptosome&#46; Once formed&#44; this complex activates the caspase-9&#44; which in turn will activate the caspase-3 to set off apoptosis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Bipolar disorder is related to the intrinsic apoptosis pathway&#59; this is known because abnormalities in the mitochondrial structure have been identified in patients that carry this disorder&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> as well as an alteration in the electron chain transport&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Not only do BDNF&#44; Nrg1 and Reelin take part in the migration of GABAergic interneurons to the cerebral cortex&#44; they induce the maturation of these neurons to promote their inclusion in specific neuron circuits&#46; Once there&#44; these molecules perform diverse functions in the mediation of synaptic connections and intracellular signalling ends in favouring neuron survival through anti-apoptotic pathways&#46; In addition&#44; the intracellular signalling of these 3 molecules depends on correct synaptic activity in the neuron in which they are found&#46; BDNF not only stimulates dendritic and axonal tropism&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> the degree of synaptic activity mediated by NMDA receptors also strengthens dendrite development&#59; this is in turn mediated by BDNF through a synergic effect&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> finally promoting connectivity between neuronas&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> BDNF stimulates the activity of calmodulin-dependent protein kinase <span class="elsevierStyleSmallCaps">ii</span> &#40;CaMKII&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> a protein that induces synaptic plasticity&#44; favouring cell survival through anti-apoptotic mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Likewise&#44; CaMKII stimulated phosphorylation and inhibition of glycogen synthase kinase-3 &#40;GSK-3&#41;&#44; as well as the inactivation of BAD&#44; both mediators of apoptosis&#44; which is a reaction dependent on neuronal depolarization&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a> In addition&#44; it has recently been determined that the brain of a patient with bipolar disorder presents a high expression of BAD and a low expression of BDNF&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> as well as a drop in mRNA CaMKII in the prefrontal cortex&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Reelin&#44; in spite of the fact that it is a extracellular matrix protein&#44; plays a crucial role in synaptic maturation during neurodevelopment&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> Its activation also promotes neuron survival when the AKT&#47;PI3-K intracellular pathway is triggered&#44; finally phosphorylating and inactivating BAD&#44; a molecule that induces apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> It was recently demonstrated that AKT&#47;PI3-K inhibition produces caspase-dependent apoptosis&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> a shared pathway for the 3 molecules under study that presented abnormal expression in the brain of a subject with bipolar disorder &#40;see above&#41;&#46; Finally&#44; Nrg1 and its receptor ErbB-4 interact directly with synaptic structures such as PSD-95 and some subunits of the NMDA receptor&#44; fostering their activation&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44&#44;45</span></a> The level of neuron activity also determines their expression&#44; principally during neurodevelopment&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> requiring electron depolarization for proteolytic cleavage of their precursor located in the neuronal membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> As the receptor agonises&#44; Nrg1 stimulates intracellular signalling of second messengers&#44; culminating in the activation of transcription factors that will mediate cell survival through PI3K&#47;AKT and Bcl-2<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#59; the latter is by nature an anti-apoptotic molecule&#44; whose expression is reduced in the brain of the bipolar patient&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0020" class="elsevierStylePara elsevierViewall">Approximately 75&#37; of all the neurons existing during neurodevelopment die as part of a normal process of synaptic refinement&#46; Scientific evidence points to apoptosis as the most attractive form of neuron death to maintain this phenomenon&#46; GABAergic interneurons have been studied in various psychiatric pathologies such as major depressive disorder&#44; bipolar disorder and schizophrenia&#46; In the specific case of bipolar disorder&#44; these interneurons are significantly reduced in the prefrontal cortex and the hippocampus&#44; a deficit that is not accompanied by anatomopathological findings of neuronal death in the adult brain&#59; this suggests that these neurons died during neurodevelopment&#44; being an abnormal exacerbation of a normal process of massive neuronal death&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Bipolar disorder typically presents at the beginning of adulthood&#44; a time when the brain is being submitted to functional and structural changes mainly determined by hormonal activity&#46; The deficit in GABAergic interneurons in the cerebral cortex of the subject with bipolar disorder would then represent an element originating in the foetal state with a clinically relevant appearance at the beginning of adulthood&#44; going unnoticed during childhood and part of adolescence&#46; Bipolar disorder is known to generate cognitive degeneration&#44; which persists even in the state of eutimia<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;52</span></a> and seems to be link that is directly proportional to the length of duration of the manic episode<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> and to the chronic course of the disorder&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> However&#44; even though it is true that these findings suggest that bipolar disorder is a neurodegenerative disease&#44; its neurophysiological bases could arise in alterations in neurodevelopment&#59; this would generate a deficit in GABAergic interneurons that would trigger a long-term stimulatory state&#44; with the consequent neuronal exitotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interests</span><p id="par0030" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "identificador" => "xres115335"
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          "titulo" => "Keywords"
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        2 => array:2 [
          "identificador" => "xres115336"
          "titulo" => "Resumen"
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        3 => array:2 [
          "identificador" => "xpalclavsec102625"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Migration of GABAergic interneurons and bipolar disorder"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Neuronal apoptosis and abnormal integration into synaptic circuits"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Conclusions"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Conflict of interests"
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        9 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2011-09-14"
    "fechaAceptado" => "2011-11-28"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec102626"
          "palabras" => array:6 [
            0 => "Apoptosis"
            1 => "Bipolar disorder"
            2 => "Neurodevelopment"
            3 => "Synapsis"
            4 => "Neuronal migration"
            5 => "GABAergic interneurons"
          ]
        ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec102625"
          "palabras" => array:6 [
            0 => "Apoptosis"
            1 => "Trastorno bipolar"
            2 => "Neurodesarrollo"
            3 => "Sinapsis"
            4 => "Migraci&#243;n neuronal"
            5 => "Interneuronas GABA&#233;rgicas"
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bipolar disorder&#44; like the majority of psychiatric disorders&#44; is considered a neuro-development disease&#46; There is an increased rate of neuronal birth and death during this development period&#46; In the particular case of the processes that determine neuronal death&#44; it is known that those neurons that establish connections have to be removed from the central nervous system&#46; There is a deficit of GABAergic interneurons in the cerebral cortex in bipolar disorder&#44; accompanied by overexpression of proapoptic genes&#46; There is also an alteration in the expression of molecules that mediate in the migration of these neurons and their inclusion in functional synapsis during the foetal stage&#46; The role of these molecules in the neuronal death pathways by apoptosis will be reviewed here in an attempt to establish biological hypotheses of the genesis of bipolar disorder&#46;</p>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El trastorno bipolar es considerado&#44; al igual que la mayor&#237;a de los trastornos psi-qui&#225;tricos&#44; una enfermedad del neurodesarrollo&#46; Durante dicho per&#237;odo&#44; existe una marcada tasa de nacimiento y muerte neuronal&#46; En el caso particular de los procesos que determinan la muerte neuronal&#44; es sabido que aquellas neuronas que establecen conexiones sin&#225;pticas aberrantes deben ser eliminadas del sistema nervioso central&#46; El trastorno bipolar cursa con un d&#233;ficit de interneuronas GABA&#233;rgicas en la corteza cerebral&#44; acompa¿nado de una sobreexpre-si&#243;n de genes proapopt&#243;ticos&#44; as&#237; como una alteraci&#243;n en la expresi&#243;n de mol&#233;culas que median la migraci&#243;n de dichas neuronas y su inclusi&#243;n en sinapsis funcionales durante el estad&#237;o fetal&#46; Aqu&#237; ser&#225; revisado el rol de dichas mol&#233;culas sobre las v&#237;as de muerte neuronal por apoptosis en la procura de establecer hip&#243;tesis biol&#243;gicas de la g&#233;nesis del trastorno bipolar&#46;</p>"
      ]
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Uribe E&#44; Wix R&#46; Migraci&#243;n neuronal&#44; apoptosis y trastorno bipolar&#46; Rev Psiquiatr Salud Ment &#40;Barc&#46;&#41;&#46; 2012&#59;5&#58;127&#8211;33&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Migration of interneurons in bipolar disorder&#58; &#40;A&#41; showing the influence of BDNF&#44; reelin and Nrg1 on the migration of GABAergic interneurons&#44; in such a way that their correct expression determines correct integration of inhibitory circuits&#44; composed mainly of glutamatergic pyramidal neurons&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;20&#44;28</span></a> &#40;B&#41; Reducing the expression of these molecules not only causes alterations in the direction of GABAergic interneuron migration&#44; it leads to insufficient maturation of these interneurons and the subsequent aberrant integration in the inhibitory circuit and&#44; consequently&#44; death by apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Anti-apoptotic pathways that are deficient in bipolar disorder&#58; the BDNF&#44; Nrg1 and Reelin receptors are transmembrane molecules associated with a tyrosine residue&#46; TrkB activation induces the phosphorylation of GSKb and its consequent exit from the destruction complex&#44; as well as the phosphorylation and inactivation of BAD&#44; a molecule that stimulates the intrinsic apoptosis pathway&#46; Both TrkB and the Nrg1 receptor stimulate PI3K activation&#44; which culminates in BAD inactivation&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a> The activity of the Reelin receptor stimulates the activation of BCL-2&#44; which prevents the Cytochrome C from leaving the mitochondria&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p>"
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es en pt

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