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

Abstract

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.

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