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array:23 [ "pii" => "S2173505012000386" "issn" => "21735050" "doi" => "10.1016/j.rpsmen.2011.11.003" "estado" => "S300" "fechaPublicacion" => "2012-04-01" "aid" => "147" "copyright" => "SEP y SEPB" "copyrightAnyo" => "2011" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Rev Psiquiatr Salud Ment. 2012;5:127-33" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 4514 "formatos" => array:3 [ "EPUB" => 12 "HTML" => 3541 "PDF" => 961 ] ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S1888989111001820" "issn" => "18889891" "doi" => "10.1016/j.rpsm.2011.11.005" "estado" => "S300" "fechaPublicacion" => "2012-04-01" "aid" => "147" "copyright" => "SEP y SEPB" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Rev Psiquiatr Salud Ment. 2012;5:127-33" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 10394 "formatos" => array:3 [ "EPUB" => 13 "HTML" => 9012 "PDF" => 1369 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Revisión</span>" "titulo" => "Migración neuronal, apoptosis y trastorno bipolar" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "127" "paginaFinal" => "133" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Neuronal migration, apoptosis and bipolar disorder" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3503 "Ancho" => 2500 "Tamanyo" => 570433 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Vías antiapoptóticas deficientes en el trastorno bipolar: los receptores para el BDNF, Nrg1 y Reelina son moléculas transmembrana asociadas a un residuo de tirosina. La activación del TrkB induce la fosforilación de GSK-B y su consecuente salida del complejo de destrucción, así como la fosforilación e inactivación de BAD, una molécula que promueve la vía intrínseca de la apoptosis. Tanto el TrkB como el receptor de la Nrg1 promueven la activación del PI3<span class="elsevierStyleHsp" style=""></span>K, que culmina en la inactivación de BAD<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48,49</span></a>. Por su parte, la actividad del receptor de la reelina promueve la activación de BCL-2, quien evita la salida del Citocromo C de la mitocondria<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a>.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ezequiel Uribe, Richard Wix" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Ezequiel" "apellidos" => "Uribe" ] 1 => array:2 [ "nombre" => "Richard" "apellidos" => "Wix" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173505012000386" "doi" => "10.1016/j.rpsmen.2011.11.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173505012000386?idApp=UINPBA00004N" ] ] "EPUB" => 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"tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "121" "paginaFinal" => "126" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Calidad de vida en pacientes con esquizofrenia de ascendencia étnica aymara en el norte de Chile" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Alejandra Caqueo-Urízar, José Gutiérrez-Maldonado, Marta Ferrer-García, Paula Fernández-Dávila" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Alejandra" "apellidos" => "Caqueo-Urízar" ] 1 => array:2 [ "nombre" => "José" "apellidos" => "Gutiérrez-Maldonado" ] 2 => array:2 [ "nombre" => "Marta" "apellidos" => "Ferrer-García" ] 3 => array:2 [ "nombre" => "Paula" "apellidos" => "Fernández-Dávila" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1888989112000225" "doi" => "10.1016/j.rpsm.2012.01.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1888989112000225?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173505012000374?idApp=UINPBA00004N" "url" => "/21735050/0000000500000002/v1_201305031531/S2173505012000374/v1_201305031531/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Neuronal migration, apoptosis and bipolar disorder" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "127" "paginaFinal" => "133" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ezequiel Uribe, Richard Wix" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Ezequiel" "apellidos" => "Uribe" "email" => array:1 [ 0 => "ezequiel.uribe@hotmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Richard" "apellidos" => "Wix" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Universidad de Carabobo, Escuela de Medicina, Departamento de Fisiología, Laboratorio de Neurofisiología, Valencia, Venezuela" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital Psiquiátrico Dr. José Ortega Duran, Campo Universitario de Barbula, Valencia, Venezuela" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Migración neuronal, apoptosis y trastorno bipolar" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3504 "Ancho" => 2500 "Tamanyo" => 595736 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Anti-apoptotic pathways that are deficient in bipolar disorder: the BDNF, Nrg1 and Reelin receptors are transmembrane molecules associated with a tyrosine residue. TrkB activation induces the phosphorylation of GSKb and its consequent exit from the destruction complex, as well as the phosphorylation and inactivation of BAD, a molecule that stimulates the intrinsic apoptosis pathway. Both TrkB and the Nrg1 receptor stimulate PI3K activation, which culminates in BAD inactivation.<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48,49</span></a> The activity of the Reelin receptor stimulates the activation of BCL-2, which prevents the Cytochrome C from leaving the mitochondria.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p>" ] ] ] "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">1,2</span></a> that involves a considerable loss of quality of life and cognitive faculties in the intermediate term. The theories that back this hypothesis represent the best approximations in the search for the molecular origins of psychiatric disorders,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</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. In bipolar disorder, there is a 27% deficit of interneurons in the cerebral cortex<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and hippocampus.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> There is also a high expression of pro-apoptotic genes<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> such as Bcl-2-associated x protein (BAX), Bcl-2-associated death promoter (BAD), caspase-9 and caspase-3, along with a decrease in the expression of anti-apoptotic genes such as brain derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2).<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> When the interneurons migrate, they require the signalling of extracellular molecules that synergically mediate their transfer and posterior incorporation to specific neuronal circuits. The protomap hypothesis formulates that a neuron, from its birth, has defined genetic instructions as to the exact place of migration and synaptic connections that it will establish when it incorporates into functional circuits,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> so that if it incorporates itself erratically to these circuits, it will establish abnormal synaptic connections that will lead to its death.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> Neuronal death represents a phenomenon needed in the central nervous system, which determines the exact number of cells that will constitute specific neuronal circuits. In spite of the fact that neuronal death is present throughout a normal subject's life, it is much more intense during neurodevelopment because of the high rate of neurogenesis in this period. There are at least 3 types of neuronal death known: apoptosis, autophagy and necrosis. With respect to mental disease and the presence of neuronal death in it, we enter into an intense debate in which the uncertainty of isolated and reductionist research, lacking an overall vision, prevail. 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>; 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. At any rate, in their migration process, interneurons require the action of molecules that stimulate cell survival, molecules with an alteration in their expression that confers a risk of having the disorder (see further on). In this review article, we present the analysis of 3 of the elements involved in bipolar disorder: BDNF, Neuregulin 1 (Nrg1) and Reelin. We also cover the pro-apoptotic pathways that trigger their abnormal expression.</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, with a fine control that guarantees not only correct migration, but also complete maturation in the search for achieving appropriate inclusion in a specific inhibitory circuit (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). BDNF plays an essential role in the way GABAergic interneurons (molecules deficient in bipolar disorder) migrate to the cortex during neurodevelopment.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In rodents lacking expression of the BDNF receptor, tropomyosin-related kinase B (TrkB), tangential migration is reduced in the embryonic period.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> BDNF production is subject to the expression of molecules of a synaptic nature, such as calcium-dependent activator protein for secretion 2 (CAPS2),<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, the greater the production of CAPS32 and, consequently, of BDNF.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Once tangential migration to the cerebral cortex has occurred, interneurons require extracellular molecule signalling to migrate radially. Reelin is a glycoprotein secreted by the Cajal-Retzius cells that links to specific receptors in the interneuron membrane to provoke radial migration.<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. The youngest neurons usually detain their migratory process in the deepest layers, while adult neurons do so in the superficial layers. This process is inverted in zero expression models for Reelin.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Consequently, despite not affecting radial and tangential migration directly, the interneurons reach an incorrect place due to the cortical layers being.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20–22</span></a> Some variations of the Reelin gene have been identified as a risk factor for developing bipolar disorder in females,<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.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In addition, some antidepressants and antipsychotics (drugs commonly used in bipolar disorder) increase Reelin expression in the prefrontal cortex.<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 (GAD) positive interneurons<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> has recently been identified; patients with bipolar disorder had up to a 40% deficit.<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,<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. 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.<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, the GABAergic interneurons should integrate in neuronal circuits to carry out a specific role. 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. Consequently, when they join that circuit, they lack the differentiation needed to establish functional synaptic connections. In any case, whether the interneurons reach the improper place or they reach the correct place and establish aberrant synaptic connections, they must be eliminated from the brain as they develop, as part of a normal synaptic refinement process (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). The prefrontal cortex in the patient with bipolar disorder presents a high expression of pro-apoptotic molecules such as BAD, BAX, caspase-3 and -9 and reduced expression of anti-apoptotic molecules such as Bcl-2.<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, justifying in this way the interneuron deficit existing in these patients. Apoptosis is triggered through 2 pathways. The first is the extrinsic, which is activated by ligands of the tumour necrosis factor family that, upon linking to its receptor in the neuronal surface, promotes caspase-8 activation; this in turn successively activates caspase-3, -6 or -7, finally inducing apoptosis. The 2nd pathway is the intrinsic or mitochondrial; when various molecules in the mitochondrial intermembrane space leave for the neuronal cytoplasm, it is activated. The main one of these molecules is Cytochrome C, which forms a complex with Apaf-1 and dATP nucleosome designated apoptosome. Once formed, this complex activates the caspase-9, which in turn will activate the caspase-3 to set off apoptosis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Bipolar disorder is related to the intrinsic apoptosis pathway; this is known because abnormalities in the mitochondrial structure have been identified in patients that carry this disorder,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> as well as an alteration in the electron chain transport.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Not only do BDNF, Nrg1 and Reelin take part in the migration of GABAergic interneurons to the cerebral cortex, they induce the maturation of these neurons to promote their inclusion in specific neuron circuits. Once there, these molecules perform diverse functions in the mediation of synaptic connections and intracellular signalling ends in favouring neuron survival through anti-apoptotic pathways. In addition, the intracellular signalling of these 3 molecules depends on correct synaptic activity in the neuron in which they are found. BDNF not only stimulates dendritic and axonal tropism,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> the degree of synaptic activity mediated by NMDA receptors also strengthens dendrite development; this is in turn mediated by BDNF through a synergic effect,<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> finally promoting connectivity between neuronas.<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> (CaMKII),<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> a protein that induces synaptic plasticity, favouring cell survival through anti-apoptotic mechanisms.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Likewise, CaMKII stimulated phosphorylation and inhibition of glycogen synthase kinase-3 (GSK-3), as well as the inactivation of BAD, both mediators of apoptosis, which is a reaction dependent on neuronal depolarization.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37,38</span></a> In addition, 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,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> as well as a drop in mRNA CaMKII in the prefrontal cortex.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Reelin, in spite of the fact that it is a extracellular matrix protein, plays a crucial role in synaptic maturation during neurodevelopment.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40,41</span></a> Its activation also promotes neuron survival when the AKT/PI3-K intracellular pathway is triggered, finally phosphorylating and inactivating BAD, a molecule that induces apoptosis.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> It was recently demonstrated that AKT/PI3-K inhibition produces caspase-dependent apoptosis,<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 (see above). Finally, Nrg1 and its receptor ErbB-4 interact directly with synaptic structures such as PSD-95 and some subunits of the NMDA receptor, fostering their activation.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44,45</span></a> The level of neuron activity also determines their expression, principally during neurodevelopment,<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.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> As the receptor agonises, Nrg1 stimulates intracellular signalling of second messengers, culminating in the activation of transcription factors that will mediate cell survival through PI3K/AKT and Bcl-2<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48,49</span></a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>); the latter is by nature an anti-apoptotic molecule, whose expression is reduced in the brain of the bipolar patient.<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% of all the neurons existing during neurodevelopment die as part of a normal process of synaptic refinement. Scientific evidence points to apoptosis as the most attractive form of neuron death to maintain this phenomenon. GABAergic interneurons have been studied in various psychiatric pathologies such as major depressive disorder, bipolar disorder and schizophrenia. In the specific case of bipolar disorder, these interneurons are significantly reduced in the prefrontal cortex and the hippocampus, a deficit that is not accompanied by anatomopathological findings of neuronal death in the adult brain; this suggests that these neurons died during neurodevelopment, being an abnormal exacerbation of a normal process of massive neuronal death.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Bipolar disorder typically presents at the beginning of adulthood, a time when the brain is being submitted to functional and structural changes mainly determined by hormonal activity. 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, going unnoticed during childhood and part of adolescence. Bipolar disorder is known to generate cognitive degeneration, which persists even in the state of eutimia<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51,52</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.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> However, even though it is true that these findings suggest that bipolar disorder is a neurodegenerative disease, its neurophysiological bases could arise in alterations in neurodevelopment; this would generate a deficit in GABAergic interneurons that would trigger a long-term stimulatory state, with the consequent neuronal exitotoxicity.<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.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres115335" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec102626" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres115336" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec102625" "titulo" => "Palabras clave" ] 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" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-09-14" "fechaAceptado" => "2011-11-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec102626" "palabras" => array:6 [ 0 => "Apoptosis" 1 => "Bipolar disorder" 2 => "Neurodevelopment" 3 => "Synapsis" 4 => "Neuronal migration" 5 => "GABAergic interneurons" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec102625" "palabras" => array:6 [ 0 => "Apoptosis" 1 => "Trastorno bipolar" 2 => "Neurodesarrollo" 3 => "Sinapsis" 4 => "Migración neuronal" 5 => "Interneuronas GABAérgicas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bipolar disorder, like the majority of psychiatric disorders, is considered a neuro-development disease. There is an increased rate of neuronal birth and death during this development period. In the particular case of the processes that determine neuronal death, it is known that those neurons that establish connections have to be removed from the central nervous system. There is a deficit of GABAergic interneurons in the cerebral cortex in bipolar disorder, accompanied by overexpression of proapoptic genes. 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. 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.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El trastorno bipolar es considerado, al igual que la mayoría de los trastornos psi-quiátricos, una enfermedad del neurodesarrollo. Durante dicho período, existe una marcada tasa de nacimiento y muerte neuronal. En el caso particular de los procesos que determinan la muerte neuronal, es sabido que aquellas neuronas que establecen conexiones sinápticas aberrantes deben ser eliminadas del sistema nervioso central. El trastorno bipolar cursa con un déficit de interneuronas GABAérgicas en la corteza cerebral, acompa¿nado de una sobreexpre-sión de genes proapoptóticos, así como una alteración en la expresión de moléculas que median la migración de dichas neuronas y su inclusión en sinapsis funcionales durante el estadío fetal. Aquí será revisado el rol de dichas moléculas sobre las vías de muerte neuronal por apoptosis en la procura de establecer hipótesis biológicas de la génesis del trastorno bipolar.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Uribe E, Wix R. Migración neuronal, apoptosis y trastorno bipolar. Rev Psiquiatr Salud Ment (Barc.). 2012;5:127–33.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3529 "Ancho" => 2500 "Tamanyo" => 493010 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Migration of interneurons in bipolar disorder: (A) showing the influence of BDNF, reelin and Nrg1 on the migration of GABAergic interneurons, in such a way that their correct expression determines correct integration of inhibitory circuits, composed mainly of glutamatergic pyramidal neurons.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,20,28</span></a> (B) Reducing the expression of these molecules not only causes alterations in the direction of GABAergic interneuron migration, it leads to insufficient maturation of these interneurons and the subsequent aberrant integration in the inhibitory circuit and, consequently, death by apoptosis.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3504 "Ancho" => 2500 "Tamanyo" => 595736 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Anti-apoptotic pathways that are deficient in bipolar disorder: the BDNF, Nrg1 and Reelin receptors are transmembrane molecules associated with a tyrosine residue. TrkB activation induces the phosphorylation of GSKb and its consequent exit from the destruction complex, as well as the phosphorylation and inactivation of BAD, a molecule that stimulates the intrinsic apoptosis pathway. 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Year/Month | Html | Total | |
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2024 November | 18 | 10 | 28 |
2024 October | 46 | 7 | 53 |
2024 September | 89 | 13 | 102 |
2024 August | 50 | 5 | 55 |
2024 July | 59 | 9 | 68 |
2024 June | 48 | 5 | 53 |
2024 May | 47 | 5 | 52 |
2024 April | 44 | 9 | 53 |
2024 March | 230 | 17 | 247 |
2024 February | 66 | 0 | 66 |
2024 January | 65 | 14 | 79 |
2023 December | 73 | 12 | 85 |
2023 November | 80 | 9 | 89 |
2023 October | 93 | 6 | 99 |
2023 September | 60 | 6 | 66 |
2023 August | 40 | 5 | 45 |
2023 July | 58 | 11 | 69 |
2023 June | 50 | 7 | 57 |
2023 May | 77 | 15 | 92 |
2023 April | 61 | 14 | 75 |
2023 March | 84 | 8 | 92 |
2023 February | 79 | 14 | 93 |
2023 January | 78 | 17 | 95 |
2022 December | 59 | 23 | 82 |
2022 November | 59 | 30 | 89 |
2022 October | 57 | 38 | 95 |
2022 September | 69 | 26 | 95 |
2022 August | 75 | 45 | 120 |
2022 July | 77 | 30 | 107 |
2022 June | 75 | 19 | 94 |
2022 May | 72 | 17 | 89 |
2022 April | 111 | 34 | 145 |
2022 March | 162 | 22 | 184 |
2022 February | 184 | 19 | 203 |
2022 January | 135 | 12 | 147 |
2021 December | 116 | 10 | 126 |
2021 November | 118 | 17 | 135 |
2021 October | 133 | 29 | 162 |
2021 September | 114 | 14 | 128 |
2021 August | 398 | 14 | 412 |
2021 July | 82 | 18 | 100 |
2021 June | 45 | 11 | 56 |
2021 May | 69 | 19 | 88 |
2021 April | 116 | 24 | 140 |
2021 March | 90 | 10 | 100 |
2021 February | 73 | 14 | 87 |
2021 January | 78 | 20 | 98 |
2020 December | 66 | 13 | 79 |
2020 November | 79 | 10 | 89 |
2020 October | 51 | 4 | 55 |
2020 September | 40 | 9 | 49 |
2020 August | 55 | 6 | 61 |
2020 July | 42 | 8 | 50 |
2020 June | 44 | 15 | 59 |
2020 May | 49 | 11 | 60 |
2020 April | 31 | 12 | 43 |
2020 March | 43 | 7 | 50 |
2020 February | 39 | 17 | 56 |
2020 January | 43 | 9 | 52 |
2019 December | 44 | 8 | 52 |
2019 November | 37 | 8 | 45 |
2019 October | 39 | 13 | 52 |
2019 September | 35 | 10 | 45 |
2019 August | 35 | 6 | 41 |
2019 July | 75 | 25 | 100 |
2019 June | 92 | 30 | 122 |
2019 May | 140 | 77 | 217 |
2019 April | 56 | 30 | 86 |
2019 March | 41 | 11 | 52 |
2019 February | 29 | 3 | 32 |
2019 January | 25 | 9 | 34 |
2018 December | 23 | 10 | 33 |
2018 November | 51 | 5 | 56 |
2018 October | 37 | 8 | 45 |
2018 September | 21 | 11 | 32 |
2018 August | 23 | 22 | 45 |
2018 July | 20 | 10 | 30 |
2018 June | 18 | 8 | 26 |
2018 May | 20 | 10 | 30 |
2018 April | 24 | 4 | 28 |
2018 March | 42 | 5 | 47 |
2018 February | 36 | 1 | 37 |
2018 January | 23 | 3 | 26 |
2017 December | 23 | 1 | 24 |
2017 November | 38 | 3 | 41 |
2017 October | 41 | 4 | 45 |
2017 September | 36 | 6 | 42 |
2017 August | 32 | 4 | 36 |
2017 July | 37 | 15 | 52 |
2017 June | 33 | 13 | 46 |
2017 May | 59 | 10 | 69 |
2017 April | 51 | 8 | 59 |
2017 March | 49 | 58 | 107 |
2017 February | 58 | 2 | 60 |
2017 January | 52 | 5 | 57 |
2016 December | 48 | 5 | 53 |
2016 November | 62 | 15 | 77 |
2016 October | 96 | 10 | 106 |
2016 September | 85 | 10 | 95 |
2016 August | 152 | 8 | 160 |
2016 July | 48 | 3 | 51 |
2016 June | 44 | 19 | 63 |
2016 May | 33 | 11 | 44 |
2016 April | 38 | 17 | 55 |
2016 March | 44 | 11 | 55 |
2016 February | 43 | 31 | 74 |
2016 January | 41 | 16 | 57 |
2015 December | 41 | 19 | 60 |
2015 November | 36 | 15 | 51 |
2015 October | 39 | 25 | 64 |
2015 September | 32 | 12 | 44 |
2015 August | 48 | 3 | 51 |
2015 July | 66 | 7 | 73 |
2015 June | 35 | 10 | 45 |
2015 May | 46 | 21 | 67 |
2015 April | 112 | 25 | 137 |
2015 March | 64 | 31 | 95 |
2015 February | 41 | 22 | 63 |
2015 January | 46 | 15 | 61 |
2014 December | 65 | 14 | 79 |
2014 November | 24 | 9 | 33 |
2014 October | 38 | 8 | 46 |
2014 September | 32 | 4 | 36 |
2014 August | 36 | 5 | 41 |
2014 July | 34 | 10 | 44 |
2014 June | 22 | 3 | 25 |
2014 May | 24 | 7 | 31 |
2014 April | 25 | 13 | 38 |
2014 March | 19 | 9 | 28 |
2014 February | 22 | 3 | 25 |
2014 January | 26 | 8 | 34 |
2013 December | 31 | 8 | 39 |
2013 November | 38 | 4 | 42 |
2013 October | 70 | 3 | 73 |
2013 September | 56 | 7 | 63 |
2013 August | 60 | 8 | 68 |
2013 July | 19 | 5 | 24 |