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1.
Brain Behav Immun ; 42: 222-31, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25066466

RESUMEN

Interferon-α (IFN-α) is a pleiotropic cytokine that is administered as a therapeutic in highly prevalent medical conditions such as chronic hepatitis C and B virus infection, melanoma and lymphoma. IFN-α induces, to a clinically relevant degree, concentration, memory, drive and mood disturbances in almost half of all patients. For this reason, IFN-α is increasingly being replaced by more specifically acting drugs. In the past decades, IFN-α has offered a valuable insight into the pathogenesis of major depression, particularly in settings associated with inflammation. IFN-α triggers immune responses, hypothalamo-pituitary-adrenal axis abnormalities and disturbances of brain metabolism resembling those in other depression states. IFN-α stimulates indoleamine-2,3 dioxygenase-1, activating the kynurenine pathway with reduced formation of the neurotransmitters serotonin and dopamine, excessive formation of the NMDA agonist quinolinic acid, and reduced formation of the NMDA antagonist kynurenic acid. In addition, IFN-α disturbs neurotrophic signaling and impedes neurite outgrowth, synaptic plasticity, endogenous neurogenesis and neuronal survival. Consequently, IFN-α-related depression may represent a model for the neurodegenerative changes that are noticed in late-life major depression. Indeed, the observation that brain responses in IFN-α-related depression resemble idiopathic depression is supported by the existence of common genetic signatures, among which of note, a number of neuronal survival and plasticity genes have been identified. In view of the high incidence of depressive symptoms, IFN-α-related depression is an attractive model for studying links between neuronal plasticity, neurodegeneration and depression. We predict that in the latter areas new targets for anti-depressant therapies could be identified, which may deepen our understanding of idiopathic major depression.


Asunto(s)
Trastorno Depresivo/etiología , Inflamación/complicaciones , Interferón-alfa/efectos adversos , Citocinas/inmunología , Trastorno Depresivo/inducido químicamente , Trastorno Depresivo/inmunología , Humanos , Inflamación/inmunología , Interferón-alfa/uso terapéutico
2.
Cell Tissue Res ; 339(2): 383-95, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20012322

RESUMEN

The subcommissural organ (SCO) is an ependymal differentiation located in the diencephalon under the posterior commissure (PC). SCO-spondin, a glycoprotein released by the SCO, belongs to the thrombospondin superfamily and shares molecular domains with axonal pathfinding molecules. Several lines of evidence suggest a relationship between the SCO and the development of the PC in the chick: (1) their close location to each other, (2) their differentiation at the same developmental stage in the chick, (3) the abnormal PC found in null mutants lacking an SCO and (4) the release by the SCO of SCO-spondin. By application of DiI crystals in the PC of chick embryos, we have identified the neurons that give rise to the PC. Labelling is confined to the magnocellular nucleus of the PC (MNPC). To gain insight into the role of the SCO in PC development, coculture experiments of explants of the MNPC region (MNPCr) from embryos at embryonic day 4 (E4) with SCO explants from E4 or E13 embryos have been performed and the neurite outgrowth from the MNPCr explants has been analysed. In the case of coculture of E4 MNPCr with E4 SCO, the number of neurites growing from the MNPCr is higher at the side facing the SCO. However, when E4 MNPCr and E13 SCO are cocultured, the neurites grow mostly at the side opposite to the SCO. These data suggest that, at early stages of development, the SCO releases some attractive or permissive molecule(s) for the growing of the PC, whereas at later stages, the SCO has a repulsive effect over neurites arising from MNPCr.


Asunto(s)
Comunicación Celular , Epitálamo/embriología , Neuronas/citología , Órgano Subcomisural/embriología , Animales , Diferenciación Celular , Embrión de Pollo , Técnicas de Cocultivo , Epitálamo/citología , Inmunohistoquímica , Neuritas/fisiología , Órgano Subcomisural/citología , Técnicas de Cultivo de Tejidos
3.
Neurobiol Learn Mem ; 94(1): 73-82, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20388543

RESUMEN

Lysophosphatidic acid (LPA) is a new, intercellular signalling molecule in the brain that has an important role in adult hippocampal plasticity. Mice lacking the LPA(1) receptor exhibit motor, emotional and cognitive alterations. However, the potential relationship among these concomitant impairments was unclear. Wild-type and maLPA(1)-null mice were tested on the hole-board for habituation and spatial learning. MaLPA(1)-null mice exhibited reduced exploration in a novel context and a defective intersession habituation that also revealed increased anxiety-like behaviour throughout the hole-board testing. In regard to spatial memory, maLPA(1) nulls failed to reach the controls' performance at the end of the reference memory task. Moreover, their defective working memory on the first training day suggested a delayed acquisition of the task's working memory rule, which is also a long term memory component. The temporal interval between trials and the task's difficulty may explain some of the deficits found in these mice. Principal components analysis revealed that alterations found in each behavioural dimension were independent. Therefore, exploratory and emotional impairments did not account for the cognitive deficits that may be attributed to maLPA(1) nulls' hippocampal malfunction.


Asunto(s)
Ansiedad/metabolismo , Conducta Exploratoria/fisiología , Trastornos de la Memoria/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Animales , Ansiedad/genética , Habituación Psicofisiológica/fisiología , Masculino , Memoria/fisiología , Trastornos de la Memoria/genética , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/fisiología , Pruebas Neuropsicológicas , Análisis de Componente Principal , Receptores del Ácido Lisofosfatídico/deficiencia , Receptores del Ácido Lisofosfatídico/genética , Percepción Espacial/fisiología , Factores de Tiempo
4.
Neuron ; 48(1): 63-75, 2005 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-16202709

RESUMEN

Chemorepulsion by semaphorins plays a critical role during the development of neuronal projections. Although semaphorin-induced chemoattraction has been reported in vitro, the contribution of this activity to axon pathfinding is still unclear. Using genetic and culture models, we provide evidence that both attraction and repulsion by Sema3B, a secreted semaphorin, are critical for the positioning of a major brain commissural projection, the anterior commissure (AC). NrCAM, an immunoglobulin superfamily adhesion molecule of the L1 subfamily, associates with neuropilin-2 and is a component of a receptor complex for Sema3B and Sema3F. Finally, we show that activation of the FAK/Src signaling cascade distinguishes Sema3B-mediated attractive from repulsive axonal responses of neurons forming the AC, revealing a mechanism underlying the dual activity of this guidance cue.


Asunto(s)
Neuronas/metabolismo , Vías Olfatorias , Semaforinas/fisiología , Núcleos Septales/citología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Axones/metabolismo , Northern Blotting/métodos , Western Blotting/métodos , Moléculas de Adhesión Celular/metabolismo , Agregación Celular/efectos de los fármacos , Agregación Celular/fisiología , Células Cultivadas , Chlorocebus aethiops , Clonación Molecular/métodos , Técnicas de Cocultivo/métodos , Inhibidores Enzimáticos/farmacología , Quinasa 1 de Adhesión Focal/metabolismo , Conos de Crecimiento/fisiología , Inmunohistoquímica/métodos , Inmunoprecipitación/métodos , Hibridación in Situ/métodos , Indoles/farmacología , Ratones , Ratones Noqueados , Neuropilina-2/metabolismo , Vías Olfatorias/crecimiento & desarrollo , Vías Olfatorias/metabolismo , Unión Proteica/fisiología , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Semaforinas/deficiencia , Núcleos Septales/crecimiento & desarrollo , Núcleos Septales/metabolismo , Transducción de Señal/fisiología , Sulfonamidas/farmacología , Transfección/métodos , Familia-src Quinasas/fisiología
5.
Mol Neurobiol ; 52(1): 318-29, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25159480

RESUMEN

Major depression is a serious side effect of interferon-α (IFN-α), which is used in the therapy of hepatitis C virus (HCV) infection. Due to the lack of reproducible animal models, the mechanisms underlying IFN-α-related depression are largely unknown. We herein established a mouse model, in which murine IFN-α (250 IU/day) and polyinosinic/polycytidylic acid (poly(I:C); 1 µg/day), a toll-like receptor-3 (TLR3) agonist that mimics the effect of HCV double-strand RNA, were continuously infused into the lateral ventricle via miniosmotic pumps over up to 14 days. The delivery of IFN-α and poly(I:C), but not of IFN-α or poly(I:C) alone, resulted in a reproducible depression-like state that was characterized by reduced exploration behavior in open-field tests, increased immobility in tail suspension and forced swimming tests, and a moderate loss of body weight. In the hippocampus and prefrontal cortex, the pro-inflammatory genes TNF-α, IL-6, tissue inhibitor of metalloproteinases-1 (Timp-1), CXC motif ligand-1 (Cxcl1), Cxcl10, and CC motif ligand-5 (Ccl5) were synergistically induced by IFN-α and poly(I:C), most pronounced after 14-day exposure. In comparison, the interferon-inducible genes of signal transducer and activator of transcription-1 (Stat1), guanylate binding protein-1 (Gbp1), proteasome subunit-ß type-9 (Psmb9), ubiquitin-conjugating enzyme E2L-6 (Ube2l6), receptor transporter protein-4 (Rtp4), and GTP cyclohydrolase-1 (Gch1), which had previously been elevated in the blood of IFN-α-treated patients developing depression, in the brains of suicidal individuals, and in primary neurons exposed to IFN-α and poly(I:C), were induced even earlier, reaching maximum levels mostly after 24 hours. We propose that interferon-inducible genes might be useful markers of imminent depression.


Asunto(s)
Depresión/inducido químicamente , Depresión/genética , Regulación de la Expresión Génica/efectos de los fármacos , Hepacivirus/fisiología , Hepatitis C/tratamiento farmacológico , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Hepacivirus/efectos de los fármacos , Leucocitos/efectos de los fármacos , Leucocitos/patología , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/patología , Péptido Hidrolasas/metabolismo , Fenotipo , Fosforilación/efectos de los fármacos , Poli I-C/efectos adversos , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos
6.
PLoS One ; 8(12): e83149, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24391741

RESUMEN

We have previously identified 15 genes that are associated with the development of severe depressive side effects during the standard therapy with interferon alpha and ribavirin in the peripheral blood of hepatitis C virus infected patients. An enhanced expression of these genes was also found in the blood of psychiatric patients suffering severe depressive episode. Herein, we demonstrate that the same depression-related interferon-inducible genes (DRIIs) are also upregulated in post-mortem brains of suicidal individuals. Using cultured mouse hippocampal and prefrontal neurons we show that costimulation with murine IFN (mIFN) and the TLR3 agonist poly(I:C) promotes the expression of the described DRIIs, at the same time inducing pro-inflammatory cytokine expression through Stat1 and Stat3 activation, promoting neuronal apoptosis. Consequently, the upregulation of selective DRIIs, production of inflammatory cytokines and inhibition of neuronal plasticity may be involved in the pathogenesis of IFN-associated depression.


Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Depresión/etiología , Depresión/genética , Interferón-alfa/efectos adversos , Suicidio , Receptor Toll-Like 3/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Niño , Citocinas/biosíntesis , Depresión/metabolismo , Femenino , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/psicología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Persona de Mediana Edad , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Poli I-C/farmacología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Receptor Toll-Like 3/agonistas , Regulación hacia Arriba/efectos de los fármacos , Adulto Joven
7.
PLoS One ; 7(6): e38668, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22701688

RESUMEN

BACKGROUND: Though an important percentage of patients with chronic hepatitis C virus (HCV) undergoing interferon (IFN) therapy develop depressive symptoms, the role of the IFN system in the pathogenesis of depressive disorders is not well understood. METHODS: 50 patients with HCV infection were treated with standard combination therapy (pegylated IFN-α2a/ribavirin). IFN-induced gene expression was analyzed to identify genes which are differentially regulated in patients with or without IFN-induced depression. For validation, PBMC from 22 psychiatric patients with a severe depressive episode (SDE) and 11 controls were cultivated in vitro with pegylated IFN-α2a and gene expression was analyzed. RESULTS: IFN-induced depression in HCV patients was associated with selective upregulation of 15 genes, including 6 genes that were previously described to be relevant for major depressive disorders or neuronal development. In addition, increased endogenous IFN-production and selective hyper-responsiveness of these genes to IFN stimulation were observed in SDE patients. CONCLUSIONS: Our data suggest that selective hyper-responsiveness to exogenous (IFN therapy) or endogenous (depressive disorders) type I IFNs may lead to the development of depressive symptoms. These data could lead to the discovery of novel therapeutic approaches to treat IFN-induced and major depressive disorders.


Asunto(s)
Trastorno Depresivo Mayor/inducido químicamente , Regulación de la Expresión Génica/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/efectos adversos , Interferón-alfa/metabolismo , Adulto , Estudios de Casos y Controles , Cartilla de ADN/genética , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Leucocitos Mononucleares/metabolismo , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no Paramétricas
8.
Int Rev Cell Mol Biol ; 296: 63-137, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22559938

RESUMEN

Growing axons navigate through the developing brain by means of axon guidance molecules. Intermediate targets producing such signal molecules are used as guideposts to find distal targets. Glial, and sometimes neuronal, midline structures represent intermediate targets when axons cross the midline to reach the contralateral hemisphere. The subcommissural organ (SCO), a specialized neuroepithelium located at the dorsal midline underneath the posterior commissure, releases SCO-spondin, a large glycoprotein belonging to the thrombospondin superfamily that shares molecular domains with axonal pathfinding molecules. Several evidences suggest that the SCO could be involved in the development of the PC. First, both structures display a close spatiotemporal relationship. Second, certain mutants lacking an SCO present an abnormal PC. Third, some axonal guidance molecules are expressed by SCO cells. Finally, SCO cells, the Reissner's fiber (the aggregated form of SCO-spondin), or synthetic peptides from SCO-spondin affect the neurite outgrowth or neuronal aggregation in vitro.


Asunto(s)
Diencéfalo/embriología , Órgano Subcomisural/embriología , Animales , Diencéfalo/citología , Diencéfalo/metabolismo , Humanos , Órgano Subcomisural/citología , Órgano Subcomisural/metabolismo
9.
PLoS One ; 6(9): e25522, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21980482

RESUMEN

BACKGROUND: The lysophosphatidic acid LPA1 receptor regulates plasticity and neurogenesis in the adult hippocampus. Here, we studied whether absence of the LPA1 receptor modulated the detrimental effects of chronic stress on hippocampal neurogenesis and spatial memory. METHODOLOGY/PRINCIPAL FINDINGS: Male LPA1-null (NULL) and wild-type (WT) mice were assigned to control or chronic stress conditions (21 days of restraint, 3 h/day). Immunohistochemistry for bromodeoxyuridine and endogenous markers was performed to examine hippocampal cell proliferation, survival, number and maturation of young neurons, hippocampal structure and apoptosis in the hippocampus. Corticosterone levels were measured in another a separate cohort of mice. Finally, the hole-board test assessed spatial reference and working memory. Under control conditions, NULL mice showed reduced cell proliferation, a defective population of young neurons, reduced hippocampal volume and moderate spatial memory deficits. However, the primary result is that chronic stress impaired hippocampal neurogenesis in NULLs more severely than in WT mice in terms of cell proliferation; apoptosis; the number and maturation of young neurons; and both the volume and neuronal density in the granular zone. Only stressed NULLs presented hypocortisolemia. Moreover, a dramatic deficit in spatial reference memory consolidation was observed in chronically stressed NULL mice, which was in contrast to the minor effect observed in stressed WT mice. CONCLUSIONS/SIGNIFICANCE: These results reveal that the absence of the LPA1 receptor aggravates the chronic stress-induced impairment to hippocampal neurogenesis and its dependent functions. Thus, modulation of the LPA1 receptor pathway may be of interest with respect to the treatment of stress-induced hippocampal pathology.


Asunto(s)
Hipocampo/patología , Memoria/fisiología , Neurogénesis , Receptores del Ácido Lisofosfatídico/deficiencia , Receptores del Ácido Lisofosfatídico/genética , Conducta Espacial/fisiología , Estrés Psicológico/complicaciones , Animales , Ansiedad/complicaciones , Ansiedad/metabolismo , Ansiedad/patología , Ansiedad/fisiopatología , Apoptosis/genética , Recuento de Células , Proliferación Celular , Supervivencia Celular/genética , Proteínas de Dominio Doblecortina , Conducta Exploratoria/fisiología , Técnicas de Inactivación de Genes , Hipocampo/metabolismo , Hipocampo/fisiopatología , Masculino , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Memoria a Corto Plazo/fisiología , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Células-Madre Neurales/patología , Neuroglía/patología , Neuronas/patología , Neuropéptidos/metabolismo , Tamaño de los Órganos/genética , Restricción Física/efectos adversos , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Estrés Psicológico/fisiopatología
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