Reelin Modulates NMDA Receptor Activity in Cortical Neurons

Abstract

Reelin, a large protein that regulates neuronal migration during embryonic development, activates a conserved signaling pathway that requires its receptors, very low-density lipoprotein receptor and apolipoprotein E receptor 2, the cytoplasmic adaptor protein Disabled-1 (Dab1), and Src family kinases (SFK). Reelin also markedly enhances long-term potentiation in the adult hippocampus, suggesting that this developmental signaling pathway can physiologically modulate learning and behavior. Here, we show that Reelin can regulate NMDA-type glutamate receptor activity through a mechanism that requires SFKs and Dab1. Reelin mediates tyrosine phosphorylation of and potentiates calcium influx through NMDA receptors in primary wild-type cortical neurons but not in Dab1 knock-out neurons or in cells in which Reelin binding to its receptors is blocked by a receptor antagonist. Inhibition of SFK abolishes Reelin-induced and glutamate-dependent enhancement of calcium influx. We also show that Reelin-induced augmentation of Ca 2ϩ entry through NMDA receptors increases phosphorylation and nuclear translocation of the transcription factor cAMP-response element binding protein. Thus, Reelin may physiologically modulate learning and memory by modulating NMDA receptor functions.

Age-related accumulation of Reelin in amyloid-like deposits

“…1), in line with the reduction of cholinergic activity accompanying normal aging and AD (Sarter and Bruno, 2004). Complementary glutamatergic changes are likely involved in age-related memory impairments, potentially via reduced Reelin-mediated modulation of NMDA receptor activity and LTP Chen et al, 2005;Weeber et al, 2002). It is conceivable that age-related reductions of Reelin indirectly affect cognitive performances by favoring the production of soluble Aβ species, shown to impair LTP (Rowan et al, 2005;Walsh et al, 2002;Wang et al, 2002).…”

“…The signal is terminated with Reelin targeted to the lysosome and Dab1 degraded by the proteasome (Arnaud et al, 2003;Bock et al, 2004;Morimura et al, 2005). In the adult brain, Reelin expression is maintained by GABAergic interneurons and glutamatergic pyramidal neurons in layer II of the entorhinal cortex (Alcantara et al, 1998;Miettinen et al, 2005;Pesold et al, 1998;Ramos-Moreno et al, 2006) and the same signalling cascade is used in adult synapses to modulate neuronal function and synaptic plasticity by regulating glutamate receptor activity through the phosphorylation of intracellular tyrosine residues (Beffert et al, , 2006Chen et al, 2005;Weeber et al, 2002).…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Other potential mechanisms by which ApoE receptors may promote neuronal survival (Beffert et al 2006b) during aging involve signaling pathways that control microtubule and actin dynamics Assadi et al 2003;Brich et al 2003;Ohkubo et al 2003;Chai et al 2009;Forster et al 2010;Rust et al 2010), dendritogenesis (Niu et al 2004), spine formation (Niu et al 2008), glutamate receptor function and synaptic plasticity (Zhuo et al 2000;Weeber et al 2002;Beffert et al 2005;Chen et al 2005;D'Arcangelo 2005;Sinagra et al 2005;Groc et al 2007;Durakoglugil et al 2009;Korwek et al 2009;Chen et al 2010), as well as learning and memory (reviewed in Herz and Beffert 2000;Herz and Chen 2006;Bu 2009;Herz 2009). In this section we will mainly focus on the role of the ApoE receptors Apoer2 and Vldlr and their ligand Reelin in these processes.…”

“…Activation of SFKs is the "master switch" that is required for the initiation of all subsequent downstream signaling events, which are not limited to the control of GSK3b activity but also involve the regulation of Lis1-dependent nuclear translocation (Shu et al 2004), n-cofilin-mediated actin reorganization (Chai et al 2009;Frotscher 2010), and tyrosine phosphorylation of NMDA receptor subunits Chen et al 2005). …”

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

“…This in turn induces phosphorylation of the adaptor protein Disabled-1 (Dab-1) (Hiesberger et al, 1999), a process that activates cytosolic kinase pathways involving (i) SRC family tyrosine kinases (SFKs), leading to phosphorylation of NMDAR subunit NR2 on the postsynaptic membrane and the concomitant potentiation of NMDAR-mediated Ca 2+ influx (Chen et al, 2005), and (ii) the activation of Phosphatidylinositol-3-kinase (PI3K) and protein kinase B (Akt/PKB) leading to inhibition of GSK3β (Beffert et al, 2002) and concomitant suppression of Tau hyperphosphorylation (Ohkubo et al, 2003), which is a key step in the formation of neurofibrillary tangles (Augustinack et al, 2002). The activaton of the Reelin pathway involving Dab-1, SFKs and PI3K also results in LIM1 kinase activation with a concomitant increase in n-cofilin phosphorylation, a signaling mechanism engaged in the leading processes of migrating neurons to stabilize the actin cytoskeleton (Chai et al, 2009).…”