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Alteraciones Sexo-Específicas En Sociabilidad Y Neuroinflamación En Un Modelo En Ratón De Autismo

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Alteraciones Sexo-Específicas En Sociabilidad Y Neuroinflamación En Un Modelo En Ratón De Autismo Universidad de Buenos Aires Facultad de Ciencias Exactas y Naturales Alteraciones sexo-específicas en sociabilidad y neuroinflamación en un modelo en ratón de autismo Tesis presentada para optar por el título de Doctor de la Universidad de Buenos Aires en el área Ciencias Biológicas Nadia Kazlauskas Directora de tesis: Dra. Amaicha Mara Depino Consejera de estudios: Dra. Lidia Szczupak Lugar de trabajo: Instituto de Fisiología, Biología Molecular y Neurociencias (IFIByNE-CONICET). Buenos Aires, 2017 1 Alteraciones sexo-específicas en sociabilidad y neuroinflamación en un modelo en ratón de autismo El autismo es un desorden del desarrollo neural caracterizado por impedimentos en la interacción social, habilidades comunicativas reducidas y la presencia de comportamientos estereotipados o repetitivos. Estos síntomas típicamente aparecen durante los primeros años de vida, y pueden afectar hasta a 1 en 38 niños, con una incidencia entre tres y cuatro veces mayor en varones que en mujeres. Actualmente no se conoce una única causa del desorden, sino que se proponen múltiples agentes etiológicos. Estudios postmortem realizados en humanos ​ han establecido un nexo entre autismo y neuroinflamación. El objetivo general de esta tesis fue dilucidar el rol de la respuesta inflamatoria del sistema nervioso central, particularmente la activación glial, en el desarrollo del autismo. Para ello utilizamos el modelo de administración prenatal de Ácido Valproico (VPA) en ratón. Encontramos que la exposición al VPA produce una disminución en la sociabilidad de los ratones macho adultos, pero no así de los ratones hembra. Además, las hembras VPA presentan micro y astrogliosis en el cerebelo, y una respuesta inflamatoria periférica exacerbada ante la administración de un estímulo inflamatorio. Sin embargo, dichas alteraciones no se encuentran presentes en los machos. Dado que los síntomas del autismo aparecen de manera temprana durante la infancia, caracterizamos el estado inflamatorio periférico y central en el período postnatal y evidenciamos signos de alteraciones gliales tempranas en cerebelo e hipocampo entre el día postnatal (P) 21 y P35. Con el fin de evaluar el efecto directo de la inflamación postnatal en los niveles de sociabilidad de los animales, administramos un estímulo inflamatorio a lo largo de dicho período crítico. Observamos que la inflamación postnatal afecta diferencialmente la interacción social 2 en los ratones VPA, dependiendo del sexo de los mismos. Mientras las hembras ven reducidos sus niveles de sociabilidad, los machos restauran sus niveles normales. Al estudiar los mecanismos moleculares mediante los cuales se encuentra actuando el VPA, encontramos una disminución en los niveles de acetilación de histonas en el cerebelo de animales P14. Dado que este fenómeno precede al período postnatal crítico, sugerimos que las alteraciones neuroinflamatorias observadas en el modelo podrían estar siendo guiadas por un mecanismo epigenético. Los resultados aquí presentados evidencian efectos sexo-específicos del VPA sobre la sociabilidad y el estado inflamatorio de los animales, tanto central como periférico. Además, se demuestran efectos diferenciales de la inflamación postnatal sobre los comportamientos sociales de machos y hembras. Dado que la mayor parte de la investigación en modelos animales de autismo ha sido desarrollada en animales macho, consideramos que este trabajo puede ayudar en la comprensión de los síntomas particulares observados en las niñas autistas, y adicionalmente aportar evidencias sobre posibles mecanismos de resiliencia dentro de la población femenina. Palabras clave: autismo, neuroinflamación, ácido valproico, modelo animal, sociabilidad, acetilación de histonas. 3 Sex-specific social and neuroinflammatory alterations in a mouse model of autism Autism is a neurodevelopmental disorder characterized by impediments in social interaction, reduced communicative skills and the presence of stereotyped or repetitive behaviors. These symptoms typically appear during the first years of childhood, and can affect 1 in 38 children. Remarkably, incidence is three to four times higher in boys than in girls. Although many factors have been implicated in this disorder, the exact underlying causes are still unclear. Postmortem studies performed in humans have established a link between autism and neuroinflammation. The general aim of this thesis was to elucidate the role of the central nervous system inflammatory response, glial activation in particular, in autism development. To do this, we used the Valproic Acid (VPA) prenatal administration mouse model. We found that VPA exposure produces decreased sociability in adult male mice, but not in females. Besides, we have found that adult female mice show increased micro and astroglial cell density in the cerebellum, and an exacerbated peripheral inflammatory response upon the administration of an inflammatory stimulus. However, these alterations are not present in male mice. Given that autism symptoms appear early in childhood, we characterized the peripheral and neuroinflammatory state along the postnatal period and found early signs of glial activation in the cerebellum and hippocampus between postnatal day (P) 21 and P35. To further explore the direct effect of postnatal inflammation on sociability, we administered an inflammatory stimulus during this critical period. We found that eliciting postnatal inflammation produces distinct behavioral outcomes depending on sex. While female mice show reduced sociability, male mice restore their normal social levels. When studying the molecular mechanisms behind VPA effects, we found a decrease in histone acetylation levels in the cerebellum of P14 animals. Given that this phenomenon precedes the postnatal critical period, we suggest that the 4 neuroinflammatory alterations present in our model could be guided by an epigenetic mechanism. The results presented here evidentiate VPA sex-specific effects on mice sociability and on the peripheral and neuroinflammatory state. Additionally, we have proven differential effects of postnatal inflammation on social behavior in male and female VPA mice. Given that most of the research on animal models of autism has been conducted in male subjects, we consider that this work could help understand the particular symptoms observed in autistic girls, and also contribute with evidences of possible resiliency mechanisms in the female population. Keywords: autism, neuroinflammation, valproic acid, animal model, sociability, histone acetylation. 5 6 Publicaciones Los resultados mostrados en esta tesis han sido incluidos total o parcialmente en las siguientes publicaciones: Trabajos publicados Postnatal behavioral and inflammatory alterations in female pups prenatally exposed to valproic acid. N. Kazlauskas, M. Campolongo, L. Lucchina, C. Zappala, A. Depino. Psychoneuroendocrinology 2016 Oct; 72:11-21. DOI: 10.1016/j.psyneuen.2016.06.001. Epub 2016 Jun 7. Trabajos en preparación Sex-specific effects of VPA on behavior and neuroinflammation: relevance for susceptibility and resilience in autism. N. Kazlauskas, M. Campolongo, A. Seiffe, A. Depino. A postnatal inflammatory event affects female mouse sociability in animals prenatally exposed to VPA. N. Kazlauskas, M. Campolongo, C. Zappala, A. Depino. Capítulos de libros Neuroinflammation in animal models of autism. N. Kazlauskas, M. Robinson-Agramonte, A. Depino. Capítulo del libro “Translational Approaches to Autism Spectrum Disorder” publicado por Springer International Publishing en enero de 2015. ISBN: 978-3-319-16320-8 7 Abreviaturas ANOVA = Analysis of Variance, análisis de la varianza ​ ​ BHE = Barrera Hematoencefálica GD = Día Gestacional GD = Giro Dentado GFAP = Glial fibrillary acidic protein, proteína ácida fibrilar glial ​ ​ HDAC = Histone deacetylases, deacetilasa de histonas ​ ​ HPA = Eje Hipotálamo-Pituitaria-Adrenal IBA1 = Anti-ionized calcium-binding adaptor molecule 1, enzima de unión a calcio 1 ​ ​ IF = Inmunofluorescencia IL-x = Interleuquina x Ip = Intraperitoneal IS = Interacción Social LNS = Lado No Social LPS = Lipopolisacárido LS = Lado Social MIA = Maternal immune activation, activación inmune materna ​ ​ P = Día Postnatal PAMPs = Pathogen-associated molecular pattern, patrones moleculares asociados a ​ ​ patógenos 8 PB = Buffer Fosfato PBS = Buffer Fosfato Salino PFA = Paraformaldehído PPA = Ácido Propiónico RIA = Radioinmunoensayo SEM = Standard Error of the Mean, error standard de la media ​ ​ SNC = Sistema Nervioso Central TBS = Buffer Tris Salino TEA = Trastornos del Espectro Autista TLRs = Receptores Toll Tx = Detergente Tritón x-100 USVs = Vocalizaciones Ultrasónicas VPA = Ácido Valproico 9 Índice 1. Introducción general 14 1.1 Trastornos del Espectro Autista (TEA) 14 1.2 Etiología 15 1.2.1 Factores genéticos 16 1.2.2 Factores ambientales 17 1.3 Respuesta inmunológica 19 1.3.1 Citoquinas 20 1.4 Neuroinflamación 21 1.4.1 Células gliales 22 1.5 Interacción entre sistema inmune y sistema nervioso 28 1.5.1 Alteraciones en pacientes con TEA 30 1.6 Modelos animales de TEA 32 1.6.1 Modelos inflamatorios de TEA 35 1.6.2 Modelos genéticos de TEA 38 1.6.3 Combinación de modelos genéticos e inflamatorios 40 1.6.4 Modelos ambientales no inflamatorios de TEA: modelo VPA 41 1.6.4.1 Antecedentes de nuestro laboratorio 43 1.7 Epigenética 44 1.7.1 Epigenética y VPA 47 Hipótesis y objetivos 50 2. Materiales y métodos 52 2.1 Animales 52 2.1.1 Obtención de los animales experimentales 52 2.2 Tratamiento prenatal 54 2.3 Tratamientos postnatales
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