# name
Role of Reelin in synaptogenesis and synaptic stabilization in the adult brain

# metadata.dc.contributor.other[].value
Universitat de Barcelona. Departament de Biologia Cel·lular

# metadata.dc.description.abstract[].value
[eng] Reelin is a high molecular weight extracellular glycoprotein that exhibits key roles both in the development of the central nervous system and in adult synaptic plasticity. Reelin expression during brain development is driven by cortical Cajal-Retzius (CR) cells (Alcantara et al., 1998). The secretion of Reelin by these cells ensures a correct splitting of the preplate into marginal zone and subplate (Del Rio et al., 1997; Super et al., 1998). Further, Reelin regulates the inside-out patterning formation of the layered cortical structures (Tissir and Goffinet, 2003). Constitutive Reelin deficit in reel ermice (Goffinet and Dernoncourt, 1991)generate an abnormally layered brain with a highly reduced cerebellum concomitant with numerous cellular ectopia(D'Arcangelo and Curran, 1998). The expression of Reelin undergoes an important change after completion of the neuronal migration processes (Alcantara et al., 1998; Soriano and Del Rio, 2005; Herz and Chen, 2006). This early suggested the existence of a new function for Reelin in the postnatal and adult brain. Heterozygous reeler(HRM)and reeler-like mice presented reduced amounts of Reelin signaling (Liu et al., 2001; Badea et al., 2007; Katsuyama and Terashima, 2009)as well as deficits in synaptic plasticity-related events, such as impairments in long-term potentiation(LTP) paradigms (Weeber et al., 2002; Beffert et al., 2005), altered phosphorylation and composition of NMDA receptors (Chen et al., 2002; Groc et al., 2007), and altered AMPA receptor-mediated responses (Qiu et al., 2006). Further, alterations in spine density were found on HRM and reeler mice (Niu et al., 2008), and adult conditional depletion of Dab1 triggers changes in their morphology (Trotter et al., 2011). More interestingly, Reelin supplementation reverts many of these phenotypes (Qiu and Weeber, 2007; Hellwig et al., 2011; Rogers et al., 2013) and adult Reelin over expression in vivo promotes enhanced LTP (Pujadas et al., 2010). Last, Reelin expression abnormalities have been reported in patients for various psychiatric disorders (Knuesel, 2010; Folsom and Fatemi, 2013).Moreover, it has been related to Alzheimer’s disease(AD) (Knuesel, 2010) and its overexpression in mouse models for ADrevealed delayed progression of the appearance of pathological insults (Pujadas et al., 2014). Here we used transgenic mice overexpressing Reelin (Pujadas et al., 2010)as well as approaches involvingconditional depletion of Dab1 in adult mice (Pramatarova et al., 2008; Teixeira et al., 2014)and in new-born granule cellsof the DG (Teixeira et al., 2012) to study the role of Reelin in the establishment and stabilization of synapses in the adult brain. In the first chapter, we analyze the role of Reelin in the molecular features and ultrastructureof the presynaptic terminals in the adult hippocampus of Reelin overexpressing (Reelin-OE) mice. We report an enhanced complexity of hippocampal boutons. In the second chapter, we analyze the role of Reelin in the molecular composition and ultrastructure of the hippocampal dendritic spines of Reelin-OE mice. We report spine hypertrophy, spine apparatus enlargement and redistribution of NMDA receptor subunits and p-cofilin. In the third chapter, we analyze the effects of Reelin signaling up-and downregulationin spine presence and morphology along two types of pyramidal cells, CA1 and S1BF layer 5. We show that Reelin regulates spine plasticity, but that the precise effects are cell-dependent and dendritic domain-specific. In the fourth chapter, we present a new approach for correlative optical microscopy (OM) –focused ion beam / scanning electron microscopy (FIB/SEM) imaging of pre-labeled dendritic segments with diaminobenzidine (DAB). We applied this method to study the synaptic integration into the preexisting circuitryof new-born DG granule cells (GCs). We report that these cells exhibit branched spines, that morphometrical parameters of a spine and synapse correlate and that spine morphologyand presynaptic innervation changes with cell development. Finally, in the fifth chapter we analyze the effects of Reelin signaling up-and down regulationin integration of new-born DG GCsinto the preexisting circuitry. We describe changes in the size and morphology of these spinesand synapses, as well as in their connectivity. REFERENCES: Alcantara S, Ruiz M, D'Arcangelo G, Ezan F, de Lecea L, Curran T, Sotelo C, Soriano E (1998) Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse.J Neurosci 18:7779-7799. Badea A, Nicholls PJ, Johnson GA, Wetsel WC (2007) Neuroanatomical phenotypes in the reeler mouse. Neuroimage 34:1363-1374. Beffert U, Weeber EJ, Durudas A, Qiu S, Masiulis I, Sweatt JD, Li WP, Adelmann G, Frotscher M, Hammer RE, Herz J (2005) Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron 47:567-579. Chen Y, Sharma RP, Costa RH, Costa E, Grayson DR (2002) On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res 30:2930-2939. D'Arcangelo G, Curran T (1998) Reeler: new tales on an old mutant mouse. Bioessays 20:235-244. Del Rio JA, Heimrich B, Borrell V, Forster E, Drakew A, Alcantara S, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Derer P, Frotscher M, Soriano E (1997) A role for Cajal-Retzius cells and reelin in the development of hippocampal connections. Nature 385:70-74. Folsom TD, Fatemi SH (2013) The involvement of Reelin in neurodevelopmental disorders. Neuropharmacology 68:122-135. Goffinet AM, Dernoncourt C (1991) Localization of the reeler gene relative to flanking loci on mouse chromosome 5. Mamm Genome 1:100-103. Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P (2007) NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin. J Neurosci 27:10165-10175. Hellwig S, Hack I, Kowalski J, Brunne B, Jarowyj J, Unger A, Bock HH, Junghans D, Frotscher M (2011) Role for Reelin in neurotransmitter release. J Neurosci 31:2352-2360. Herz J, Chen Y (2006) Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci 7:850-859. Katsuyama Y, Terashima T (2009) Developmental anatomy of reeler mutant mouse. Dev Growth Differ 51:271-286. Knuesel I (2010) Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases. Prog Neurobiol 91:257-274. Liu WS, Pesold C, Rodriguez MA, Carboni G, Auta J, Lacor P, Larson J, Condie BG, Guidotti A, Costa E (2001) Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse. Proc Natl Acad Sci U S A 98:3477-3482. Niu S, Yabut O, D'Arcangelo G (2008) The Reelin signaling pathway promotes dendritic spine developmentin hippocampal neurons. J Neurosci 28:10339-10348. Pramatarova A, Chen K, Howell BW (2008) A genetic interaction between the APP and Dab1 genes influences brain development. Mol Cell Neurosci 37:178-186. Pujadas L, Gruart A, Bosch C, Delgado L, Teixeira CM, Rossi D, de Lecea L, Martinez A, Delgado-Garcia JM, Soriano E (2010) Reelin regulates postnatal neurogenesis and enhances spine hypertrophy and long-term potentiation. J Neurosci 30:4636-4649. Pujadas L, Rossi D, Andres R, Teixeira CM, Serra-Vidal B, Parcerisas A, Maldonado R, Giralt E, Carulla N, Soriano E (2014) Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer's disease. Nat Commun 5:3443. Qiu S, WeeberEJ (2007) Reelin signaling facilitates maturation of CA1 glutamatergic synapses. J Neurophysiol 97:2312-2321. Qiu S, Zhao LF, Korwek KM, Weeber EJ (2006) Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus. J Neurosci 26:12943-12955. Rogers JT, Zhao L, Trotter JH, Rusiana I, Peters MM, Li Q, Donaldson E, Banko JL, Keenoy KE, Rebeck GW, Hoe HS, D'Arcangelo G, Weeber EJ (2013) Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse. J Psychopharmacol 27:386-395. Soriano E, Del Rio JA (2005) The cells of cajal-retzius: still a mystery one century after. Neuron 46:389-394. Super H, Martinez A, Del Rio JA, Soriano E (1998) Involvement of distinct pioneer neurons in the formation of layer-specific connections in the hippocampus. J Neurosci 18:4616-4626. Teixeira CM, Masachs N, Muhaisen A, Bosch C, Perez-Martinez J, Howell B, Soriano E (2014) Transient downregulation of Dab1 protein levels during development leads to behavioral and structural deficits: relevance for psychiatric disorders. Neuropsychopharmacology 39:556-568. Teixeira CM, Kron MM, Masachs N, Zhang H, Lagace DC, Martinez A, Reillo I, Duan X, Bosch C, Pujadas L, Brunso L, Song H, Eisch AJ, Borrell V, Howell BW, Parent JM, Soriano E (2012) Cell-autonomous inactivation of the reelin pathway impairs adult neurogenesis in the hippocampus. J Neurosci 32:12051-12065. Tissir F, Goffinet AM (2003) Reelin and brain development. Nat Rev Neurosci 4:496-505. Trotter JH, Klein M, Jinwal UK, Abisambra JF, Dickey CA, Tharkur J, Masiulis I, Ding J, Locke KG, Rickman CB, Birch DG, Weeber EJ, Herz J (2011) ApoER2 function in the establishment and maintenance of retinal synaptic connectivity. JNeurosci 31:14413-14423. Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, Herz J (2002) Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem 277:39944-39952.

# metadata.dc.source[].value
Tesis Doctorals - Departament - Biologia Cel·lular

# metadata.dc.title[].value
Role of Reelin in synaptogenesis and synaptic stabilization in the adult brain