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Role of Reelin in Synaptogenesis and Synaptic Stabilization in the Adult Brain

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Role of Reelin in Synaptogenesis and Synaptic Stabilization in the Adult Brain Role of Reelin in synaptogenesis and synaptic stabilization in the adult brain Carles Bosch Aquesta tesi doctoral està subjecta a la llicència Reconeixement- NoComercial – CompartirIgual 3.0. Espanya de Creative Commons. Esta tesis doctoral está sujeta a la licencia Reconocimiento - NoComercial – CompartirIgual 3.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0. Spain License. UNIVERSITAT DE BARCELONA FACULTAT DE BIOLOGIA DEPARTAMENT DE BIOLOGIA CEL·LULAR INSTITUTE FOR RESEARCH IN BIOMEDICINE, BARCELONA PARC CIENTÍFIC DE BARCELONA Role of Reelin in synaptogenesis and synaptic stabilization in the adult brain Carles Bosch Barcelona, juny 2014 Programa de Doctorat en Biomedicina III UNIVERSITAT DE BARCELONA FACULTAT DE BIOLOGIA DEPARTAMENT DE BIOLOGIA CEL·LULAR INSTITUTE FOR RESEARCH IN BIOMEDICINE, BARCELONA PARC CIENTÍFIC DE BARCELONA Role of Reelin in synaptogenesis and synaptic stabilization in the adult brain Paper de la Reelina en la formació i estabilització de sinapsis en el cervell adult Programa de Doctorat en Biomedicina Memòria presentada per Carles Bosch, llicenciat en Biotecnologia, per optar al grau de Doctor per la Universitat de Barcelona Els estudis de tercer cicle s’han emmarcat en el programa de doctorat en Biomedicina de la Universitat de Barcelona. El projecte de Tesi Doctoral està inscrit al Departa- ment de Biologia Cel·lular de la Facultat de Biologia de la Universitat de Barcelona. El treball experimental i la redacció de la memòria que es presenten han estat dirig- its pel Dr. Albert Martínez Garcia, Professor Agregat a la Universitat de Barcelona, i pel Dr. Eduardo Soriano García, Catedràtic de Biologia Cel·lular de la Universitat de Barcelona. Barcelona, juny de 2014. Vist-i-plau dels directors de la tesi: Dr. Albert Martínez Garcia Dr. Eduardo Soriano García El Candidat a Doctor, Carles Bosch Piñol V Als pares, al Sergi, i a la Bea. VII Quan surts per fer el viatge cap a Ítaca, has de pregar que el camí sigui llarg, ple d'aventures, ple de coneixences. (...) Caminante, son tus huellas Has d'arribar-hi, és el teu destí, el camino, y nada más; però no forcis gens la travessia. caminante, no hay camino: És preferible que duri molts anys, se hace camino al andar. que siguis vell quan fondegis l'illa, ric de tot el que hauràs guanyat fent el camí, sense esperar que et doni més riqueses. Al andar se hace camino, (...) y al volver la vista atrás Més lluny, heu d'anar més lluny se ve la senda que nunca dels arbres caiguts que ara us empresonen, se ha de volver a pisar. (...) I quan sereu deslliurats torneu a començar els nous passos. Caminante, no hay camino, Més lluny, sempre molt més lluny, sino estelas en la mar. més lluny del demà que ara ja s'acosta. I quan creieu que arribeu, sapigueu trobar noves sendes. A. Machado Kavafis - Carles Riba - Lluís Llach Agraïments Aquests han estat uns anys intensos i emocionants, durant els quals han vingut, han marxat i s’han quedat nombrosos actors parcials d’aquesta tesi. A ells van dirigides aquestes breus paraules. En primer lloc, voldria agraïr als directors de tesi la oportunitat rebuda. A l’Eduardo, per haver-me obert les portes d’aquest laboratori, i a l’Albert per la paciència mostrada i demostrada. I a tots dos, per haver dirigit els meus primers passos dins de la carrera científica. Als companys de laboratori. A TOTS. GRÀCIES. En una feina que no és individual, i que està plagada d’errors i contratemps, poder comptar amb un equip humà d’aquest nivell és més que un luxe. Em deixaré gent, però doneu-vos per aludits. Però si hem de dir noms... comencem pel principi. El primer equip de ex-predoctors, Anna, Ale, Vane... i els “grans” que ja van arribar crescudets, Cátia, Ana, Franc, i els que ja estaven crescuts quan vaig ar- ribar, Lluís, Ash. Vàreu ser els primers contactes amb algú que ja havia passat pel clot, i fent gala de l’experiència vau advertir de perills i amenaces (prohibit començar experiments més enllà de les 20h!), vau guiar passos insegurs (quants protocols de WB calen per fer-ne un?) i vau permetre luxes primer- encs (creo que con el siguiente sueldo ya me tocará devolver mojitos a alguien... ;D). I també els que han arribat més tard, però s’han guanyat un lloc enorme. Ramon, ets un crack. Tot i que en el pot petit hi va la bona confitura... i aquí em falten paraules per descriure el que ha set aquesta colla de novatos que hem pujat junts. Óscar, amfitrió de les jornades L’Hos Pintxos (cal fer-ne una International Edition!), Román, superhéroe sin complejos, fonts inacabables de motivació com la Sara o el Martí, liantes capaços de tot i més (menys quan fa pal), la delegació de la bella Italia, els “Tonis”, el Toni (et quedes de guardià!), la Mar, vida paral·lela gairebé (necessitaràs algú que piqui la cadira de tant en tant?), la Núria (sí, has d’anar al costat de la Mar, i tant), els tècnics que han ajudat dins i fora el lab, Natalia. Repetim? jejej... En segundo lugar, también agradecer a Javier abrirme las puertas de su laboratorio en tantas oca- siones, por los libros y por los consejos. A Ángel, por el trabajo impecable y dejar que jugara con ese microscopio. Y por las conversaciones sobre viejas cámaras... Y a Isabel, por el día a día. Y a Asta, por XI hacerme de taxista y profesora de microinyección a tiempo parcial. Y a toda la plantilla del laboratorio, Paula, Lidia (habrá que hacer una inmersión algún día no?), Gonzalo... Gracias por la acogida. También a gente como Alfonso o Ignacio, que sin tener nada que ver con este trabajo me habéis dedi- cado un poco de vuestro tiempo y experiencia. Y por las cervezas también. Seria injust no parlar de les plataformes tècniques on s’han desenvolupat gran part dels experiments. Pel nivell tècnic, per l’habilitat comunicativa, i per l’ambient humà. A la plataforma de microscòpia electrònica, des de la Carmen fins la Lídia, passant per tots. I a la de microscòpia digital avançada (“els confos” pels entesos). Lídia, Seb, Anna, Julien. No sabria dir què ompliria realment les pàgines que seguiexen a aquesta sense la vostra col·laboració, suport i discussió. Però no ens quedarem al laboratori. Els pisos per on he passat m’han permès conèixer gent excep- cional. La terrasseta de Maurici, Can Caballero amb el foc a terra i la play... Amb vosaltres he compartit alegries i penes durant tot aquest temps, i en guardaré un record increïble. Voldria mencionar als am- ics de sempre, els que et fan saber qui ets. Als de Puigverd, que ens coneixem des del bressol i seguim reunint-nos a desenes. I als tres de Lleida, Godo, Jose i Isaac. Fer fer fàcil l’impossible, i atractives les bajanades. Per ser capaços d’imaginar el món de l’inrevés. I sobretot, als meus. Als tiets i tietes, cosins i cosines. Per ser-hi, per preocupar-vos, per formar part de mi. Als padrins i padrines, a tots quatre. Per fer de la vida un lloc bonic per viure-hi. Al Sergi. Perquè és una passada tenir-te de germà. Ets genial, sàpigues-ho. Ah, i per la maquetació de la tesi, que no és poca cosa! ;) Als pares. Per haver-me ensenyat a viure, a ser feliç, a treballar i a estimar. I a la Bea. Per ser-hi. Per no ser com jo. Per complementar-me. Per aguantar-me quan em faig pesat. I perquè sense tu no seria jo, i per tant aquesta tesi tampoc seria la que és. A tots, GRÀCIES. XII Indexes 1 2 Index of Contents Indexes 1 Index of Contents 3 Index of Figures and Tables 9 Index of abbreviations 13 Introduction 17 1. Synapse formation during development 19 The compartmentalized brain: Patterning process of the nervous system 19 Generation and survival of nerve cells. 19 Axon guidance: how to find the target 20 Synapse formation 20 Synaptic compartmentalization: helping cells do the right choice 20 Synapse development 22 Excitatory synapses 23 Inhibitory synapses 25 Signal integration: To fire or not to fire, this is the question 25 Location of synapses depends on synapse type 26 Dendritic spines: function 26 Spinogenesis during development 27 Purkinje cells and the Sotelo model 28 Pyramidal neurons: the Miller/Peters Model and the Filopodial Model. 28 2. Spine and synapse plasticity in the adult brain 31 Spine plasticity in the adult: learning rules and plasticity 31 Molecular effectors in synaptic plasticity 33 Ca2+ dynamics 33 Actin and ABPs: the compartmentalized spinoskeleton 34 Glutamate receptors during synaptic plasticity 35 3. Reelin: Functions in the developing and adult brain 39 The Reelin pathway and its role in brain development 39 Molecular biology of Reelin: the gene, the mRNA, the protein 39 The Reelin pathway: receptors, Dab1 and signaling cascades 40 The Reelin expression and function in brain development 41 3 Reelin in the adult brain 43 The Reelin expression and function in the adult brain 43 Reelin and synaptic plasticity 44 Reelin and dendritic spines 45 Reelin and brain pathologies 47 Animal tools to study the role of the Reelin pathway in the adult brain 48 Adult-specific conditional overexpression of Reelin: The Reelin-OE mouse model 48 Conditional deletion of Dab1: floxed Dab1 mouse model-based approaches 48 Aims of the study 53 Results 57 1. Role of Reelin in the presynaptic connectivity of the adult hippocampus 59 Reelin over-expression modulates the structural complexity of presynaptic elements 59 Presynaptic proteins in Reelin-OE mice: Synapsin and SNAP25.
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