Identificación de factores genéticos en la etiología de la esquizofrenia identification of genetic factors in the etiology of schizophrenia

RESUMEN La esquizofrenia es un trastorno mental que afecta aproximadamente al 1 % de la población mundial. Está caracterizada por episodios psicóticos, en los cuales los individuos presentan alucinaciones y/o delirios. A su vez, este trastorno involucra un fuerte componente de disfunción social, falta de motivación y profundas deficiencias cognitivas. Las causas de este trastorno se desconocen a ciencia cierta, aunque la evidencia acumulada indica que surge por alteraciones en el desarrollo del sistema nervioso central. Entre los factores que incrementan el riesgo a desarrollar este trastorno se encuentran varios elementos del ambiente incluyendo, infecciones y malnutrición prenatal, así como complicaciones durante el parto. Sin embargo, estudios detallados han corroborado la existencia de factores genéticos involucrados en el desarrollo de la esquizofrenia y señalan a estos como los factores más importantes que parecen determinar la aparición de la enfermedad. A pesar de esto, la identificación de genes involucrados en el desarrollo de esta enfermedad ha resultado ser una de las tareas más difíciles que enfrentan la genética y la genómica. El desarrollo de técnicas modernas para el estudio del genoma humano ha permitido estudiar de forma sistemática las variaciones en la secuencia y estructura del genoma que dan lugar a la esquizofrenia, permitiendo la identificación de cientos de genes, que pueden estar involucrados en el desarrollo de la enfermedad. Además, se ha sugerido que muchos de estos genes están involucrados en varias enfermedades mentales que en la actualidad se diagnostican como trastornos diferentes, pero cuyo substrato biológico pudiera ser similar. Palabras clave: esquizofrenia, deleciones, desarrollo, duplicaciones, polimorfismos. ABSTRACT Schizophrenia is a mental disorder that affects approximately 1% of the worldwide population. It is characterized by psychotic episodes in which individuals have hallucinations or delusions. This disorder also involves a strong element of social dysfunction, lack of motivation and profound cognitive deficits. The causes of this disorder remain largely unknown, but evidence indicates that arises from changes in the development of the central nervous system. Among the identified risk factors for this disorder are several environmental events, including prenatal infections and malnutrition, and complications during childbirth. However, the most important factor seems to be genetics. Despite this, the identification of genes involved in the development of this disorder has emerged as one of the most difficult tasks facing modern genetics and genomics. The development of techniques for studying the human genome has allowed a more systematic approach to determine variations in the genome sequence and structure that area casually involved in schizophrenia. These studies suggest the participation hundreds of genes in schizophrenia development. In addition, it has been suggested that many of these genes are involved in various mental illnesses that today are diagnosed as separate entities, but whose biological substrate may be shared. Key words: schizophrenia, deletions, development, duplications, polymorphisms

Prenatal Inflammation-Induced Hypoferremia Alters Dopamine Function in the Adult Offspring in Rat: Relevance for Schizophrenia

Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans

Inhibition of group I metabotropic glutamate receptors reverses autistic-like phenotypes caused by deficiency of the translation repressor eIF4E binding protein 2

Exacerbated mRNA translation during brain development has been linked to autism spectrum disorders (ASDs). Deletion of the eukaryotic initiation factor 4E (eIF4E)-binding protein 2 gene (Eif4ebp2), encoding the suppressor of mRNA translation initiation 4E-BP2, leads to an imbalance in excitatory-to-inhibitory neurotransmission and ASD-like behaviors. Inhibition of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5 reverses the autistic phenotypes in several ASD mouse models. Importantly, these receptors control synaptic physiology via activation of mRNA translation. We investigated the potential reversal of autistic-like phenotypes in Eif4ebp2(−/−) mice by using antagonists of mGluR1 (JNJ16259685) or mGluR5 (fenobam). Augmented hippocampal mGluR-induced long-term depression (LTD; or chemically induced mGluR-LTD) in Eif4ebp2(−/−) mice was rescued by mGluR1 or mGluR5 antagonists. While rescue by mGluR5 inhibition occurs through the blockade of a protein synthesis-dependent component of LTD, normalization by mGluR1 antagonists requires the activation of protein synthesis. Synaptically induced LTD was deficient in Eif4ebp2(−/−) mice, and this deficit was not rescued by group I mGluR antagonists. Furthermore, a single dose of mGluR1 (0.3 mg/kg) or mGluR5 (3 mg/kg) antagonists in vivo reversed the deficits in social interaction and repetitive behaviors (marble burying) in Eif4ebp2(−/−) mice. Our results demonstrate that Eif4ebp2(−/−) mice serve as a relevant model to test potential therapies for ASD symptoms. In addition, we provide substantive evidence that the inhibition of mGluR1/mGluR5 is an effective treatment for physiological and behavioral alterations caused by exacerbated mRNA translation initiation. SIGNIFICANCE STATEMENT Exacerbated mRNA translation during brain development is associated with several autism spectrum disorders (ASDs). We recently demonstrated that the deletion of a negative regulator of mRNA translation initiation, the eukaryotic initiation factor 4E-binding protein 2, leads to ASD-like behaviors and increased excitatory synaptic activity. Here we demonstrated that autistic behavioral and electrophysiological phenotypes can be treated in adult mice with antagonists of group I metabotropic glutamate receptors (mGluRs), which have been previously used in other ASD models (i.e., fragile X syndrome). These findings support the use of group I mGluR antagonists as a potential therapy that extends to autism models involving exacerbated mRNA translation initiation

Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E

Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2 -/-), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety-and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses

IDENTIFICACIÓN DE FACTORES GENÉTICOS EN LA ETIOLOGÍA DE LA ESQUIZOFRENIA

RESUMEN La esquizofrenia es un trastorno mental que afecta aproximadamente al 1 % de la población mundial. Está caracterizada por episodios psicóticos, en los cuales los individuos presentan alucinaciones y/o delirios. A su vez, este trastorno involucra un fuerte componente de disfunción social, falta de motivación y profundas deficiencias cognitivas. Las causas de este trastorno se desconocen a ciencia cierta, aunque la evidencia acumulada indica que surge por alteraciones en el desarrollo del sistema nervioso central. Entre los factores que incrementan el riesgo a desarrollar este trastorno se encuentran varios elementos del ambiente incluyendo, infecciones y malnutrición prenatal, así como complicaciones durante el parto. Sin embargo, estudios detallados han corroborado la existencia de factores genéticos involucrados en el desarrollo de la esquizofrenia y señalan a estos como los factores más importantes que parecen determinar la aparición de la enfermedad. A pesar de esto, la identificación de genes involucrados en el desarrollo de esta enfermedad ha resultado ser una de las tareas más difíciles que enfrentan la genética y la genómica. El desarrollo de técnicas modernas para el estudio del genoma humano ha permitido estudiar de forma sistemática las variaciones en la secuencia y estructura del genoma que dan lugar a la esquizofrenia, permitiendo la identificación de cientos de genes, que pueden estar involucrados en el desarrollo de la enfermedad. Además, se ha sugerido que muchos de estos genes están involucrados en varias enfermedades mentales que en la actualidad se diagnostican como trastornos diferentes, pero cuyo substrato biológico pudiera ser similar. Palabras clave: esquizofrenia, deleciones, desarrollo, duplicaciones, polimorfismos

Prenatal inflammation and neurodevelopmental disorders: The role of cytokines

Prenatal infection has been linked to the development of schizophrenia in the offspring, most likely through the maternal inflammatory response triggered by infection. A number of studies in animal models demonstrated that acute inflammatory episodes were sufficient to trigger brain alterations in the adult offspring, especially in the mesolimbic dopamine (DA) system, involved in the pathophysiology of schizophrenia. The aim of this research program was to identify which elements of the maternal inflammatory response are implicated in the alteration of the mesolimbic DA neurotransmission of the offspring. The pro-inflammatory interleukin (IL)-6, the anti-inflammatory IL-1 receptor antagonist (ra) and the immune modulator leptin were of particular interest. To investigate this, a model of aseptic clinical trauma was used, which consisted of a localized intramuscular injection of turpentine oil (TURP). This approach allows for the study of the endogenous mediators whilst avoiding the direct targeting of the foetal compartment, since the exogenous immunogen remains at the site of injection. In the work presented here it was demonstrated that maternal inflammatory response to TURP varied with the gestational day (GD), which was associated with the magnitude of the behavioural effects in the offspring. Early TURP treatment, at GD 15, induced significant impairments in pre-pulse inhibition and the cued-task of the Morris-water maze, whereas it enhanced cued-fear conditioning and locomotor response to AMPH; these effects were largely absent when TURP was given to the dam at GD 18. Neutralization of IL-6 and IL-1ra, the main circulating mediators induced by TURP, during the maternal acute inflammatory response at GD 15 prevented the effects of prenatal TURP on enhanced locomotor response to AMPH and increased synthesis of DA in the nucleus accumbens of the offspring. Leptin, a cytokine-like hormone implicated in inflammation, appeared to be involved in the induction of enhanced behavioural plasticity following repeated AMPH administration. Finally, it was demonstrated that inflammation induced an IL-6-mediated hypoferremia that was involved in the induction of enhanced sensitization to AMPH and tyrosine hydroxylase in the nucleus accumbens. Collectively, the work presented in this thesis provides extensive and novel evidence showing that several immune mediators affect neurodevelopment of the mesolimbic DA system directly or via secondary mechanisms, and may be involved in the increased risk for schizophrenia in the human population.L'infection chez la mère a été liée au développement de la schizophrénie chez l'enfant, probablement due à la réponse inflammatoire déclenchée par l'infection. De nombreuses études utilisant des modèles animaux ont démontré que l'inflammation est suffisante pour déclencher des altérations dans le cerveau chez la progéniture adulte, en particulier dans le système dopaminergique mésolimbique (DA), impliqué dans la physiopathologie de la schizophrénie. L'objectif de ce programme de recherche était d'identifier quels éléments de la réponse inflammatoire sont impliqués dans les changements observés dans la neurotransmission DA de la progéniture. La cytokine pro-inflammatoire interleukine (IL)-6, l'antagoniste du récepteur de l'IL-1 (IL-1ra) et la leptine ont été d'un intérêt particulier. Pour induire une réponse inflammatoire, un modèle de traumatisme clinique aseptique a été utilisé. Il s'agissait d'une injection intramusculaire de l'essence de térébenthine (TURP), qui évite de cibler directement le compartiment fœtal par l'immunogène. Dans le travail présenté ici, il a été démontré que la réponse inflammatoire maternelle induite par la TURP varie selon le jour de gestation (JG), où celle-ci a été associée à l'ampleur des effets sur le comportement de la progéniture. Lorsque administré au JG 15, la TURP a induite des déficiences importantes dans l'inhibition de pré-pulse et dans le labyrinthe aquatique de Morris, alors qu'elle a accentué la peur conditionnée et la réponse locomotrice à l'AMPH. Ces effets ont été largement absents lorsque la TURP a été donnée au JG 18. La neutralisation de l'IL-6 et de l'IL-1ra lors de la réponse inflammatoire de la mère au JG 15 a empêché les effets de la TURP sur la réponse locomotrice à l'AMPH et l'augmentation de la synthèse de DA dans le noyau accumbens de la progéniture. La leptine quand à elle, semble être impliquée dans l'induction de la plasticité comportementale après des administrations répétées d'AMPH. Finallement, il a été démontré que l'inflammation déclenche l'hypoferremie, une réduction de fer dans la circulation et le placenta, qui a été impliqué dans l'induction de la sensibilisation à l'AMPH et à l'hydroxylase de tyrosine dans le noyau accumbens. Collectivement, le travail présenté dans cette thèse fournit de nombreux et nouveaux éléments montrant que plusieurs médiateurs immunitaires affectent le développement neurologique du système DA et peuvent être impliqués dans le risque accru de schizophrénie dans la population

Maternal Immune Activation and the Development of Dopaminergic Neurotransmission of the Offspring: Relevance for Schizophrenia and Other Psychoses

Prenatal infections have been linked to the development of schizophrenia (SCZ) and other neurodevelopmental disorders in the offspring, and work in animal models indicates that this is to occur through the maternal inflammatory response triggered by infection. Several studies in animal models demonstrated that acute inflammatory episodes are sufficient to trigger brain alterations in the adult offspring, especially in the mesolimbic dopamine (DA) system, involved in the pathophysiology of SCZ and other disorders involving psychosis. In the current review, we synthesize the literature on the clinical studies implicating prenatal infectious events in the development of SCZ. Then, we summarize evidence from animal models of maternal immune activation (MIA) and the behavioral and molecular alterations relevant for the function of the DAergic system. Furthermore, we discuss the evidence supporting the involvement of maternal cytokines, such as interleukin 6 (IL-6) and leptin (a hormone with effects on inflammation) in mediating the effects of MIA on the fetal brain, leading to the long-lasting effects on the offspring. In particular, IL-6 has been involved in mediating the effects of MIA animal models in the offspring through actions on the placenta, induction of IL-17a, or triggering the decrease in non-heme iron (hypoferremia). Maternal infection is very likely interacting with additional genetic and environmental risk factors in the development of SCZ; systematically investigating how these interactions produce specific phenotypes is the next step in understanding the etiology of complex psychiatric disorders

Time-Dependent Effects of Localized Inflammation on Peripheral Clock Gene Expression in Rats

<div><p>Many aspects of the immune system, including circulating cytokine levels as well as counts and function of various immune cell types, present circadian rhythms. Notably, the mortality rate of animals subjected to high doses of lipopolysaccharide is dependent on the time of treatment. In addition, the severity of symptoms of various inflammatory conditions follows a daily rhythmic pattern. The mechanisms behind the crosstalk between the circadian and immune systems remain elusive. Here we demonstrate that localized inflammation induced by turpentine oil (TURP) causes a time-dependent induction of interleukin (IL)-6 and has time-, gene- and tissue-specific effects on clock gene expression. More precisely, TURP blunts the peak of <i>Per1</i> and <i>Per2</i> expression in the liver while in other tissues, the expression nadir is elevated. In contrast, <i>Rev-erbα</i> expression remains relatively unaffected by TURP treatment. Co-treatment with the anti-inflammatory agent IL-1 receptor antagonist (IL-1Ra) did not alter the response of <i>Per2</i> to TURP treatment in liver, despite the reduced induction of fever and IL-6 serum levels. This indicates that the TURP-mediated changes of <i>Per2</i> in the liver might be due to factors other than systemic IL-6 and fever. Accordingly, IL-6 treatment had no effect on clock gene expression in HepG2 liver carcinoma cells. Altogether, we show that localized inflammation causes significant time-dependent changes in peripheral circadian clock gene expression, via a mechanism likely involving mediators independent from IL-6 and fever.</p> </div