NMDA Receptor Surface Trafficking and Synaptic Subunit Composition Are Developmentally Regulated by the Extracellular Matrix Protein Reelin

Abstract

During postnatal development, changes in the subunit composition of glutamate receptors of the NMDA subtype (NMDARs) are key to the refinement of excitatory synapses. Hypotheses for maturation of synaptic NMDARs include regulation of their expression levels, membrane targeting, and surface movements. In addition, several members of extracellular matrix (ECM) proteins such as Reelin are involved in synaptic plasticity. However, it is not known whether and how ECM proteins regulate synaptic NMDAR maturation. To probe the participation of NMDARs to synaptic currents and NMDARs surface dynamics, we used electrophysiological recordings and singleparticle tracking in cultured hippocampal neurons. Our results show that, during maturation, Reelin orchestrates the regulation of subunit composition of synaptic NMDARs and controls the surface mobility of NR2B subunits. During postnatal maturation, we observed a marked decrease of NR1/NR2B receptor participation to NMDAR-mediated synaptic currents concomitant with the accumulation of Reelin at active synapses. Blockade of the function of Reelin prevented the maturation-dependent reduction in NR1/NR2B-mediated synaptic currents. The reduction of NR1/NR2B receptors was not inhibited by blocking synaptic activity but required ␤1-containing integrin receptors. Single-particle tracking showed that inhibition of Reelin decreased the surface mobility of native NR2B-containing NMDARs, whereas their synaptic dwell time increased. Conversely, recombinant Reelin dramatically reduced NR2B-mediated synaptic currents and the time spent by NR2B subunits within synapses. Our data reveal a new mode of control of synaptic NMDAR assembly at postnatal hippocampal synapses and an unprecedented role of ECM proteins in regulating glutamate receptor surface diffusion.

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

“…Although synaptic AMPA receptor mobility is not affected, diffusion of extrasynaptic AMPA receptors is reduced owing to F-actin stabilization, preventing efficient egress of AMPA receptors from the synaptic into the extrasynaptic domain, and thus LTD, in the n-cofilin mutants. Similarly, Reelin has been shown to regulate surface mobility and synaptic residency of NMDA receptor NR2B subunits (Groc et al 2007). It is thus required for NMDA receptor maturation (Sinagra et al 2005) and for the maintenance of normal NR2A/B ratios (Campo et al 2009).…”

“…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.…”

Reelin signaling antagonizes β-amyloid at the synapse

“…1B, closed circles). This suppression was again fully reversible by co-application of Reelin (closed triangles), indicating that LTP suppression induced by low concentrations of A␤ 1-42 or A␤ [25][26][27][28][29][30][31][32][33][34][35] was not caused by a non-specific cytotoxic effect.We have reported earlier (20) that Reelin increases tyrosine phosphorylation of NR2A as well as NR2B subunits (Fig. 2A, lane 2, Upper and Lower, respectively).…”

N-acetyl-cysteine prevents pyramidal cell disarray and reelin-immunoreactive neuron deficiency in CA3 after prenatal immune challenge in rats

“…Articles afferents, and glutamate transmission (21)(22)(23)26). Deficiencies of reelin expression could also be responsible for a large range of neurodevelopmental issues (17), and the heterozygous (Reel +/− ) mouse (30), exhibiting a permanent disruption of reelin expression, is considered to be a model of schizophrenia.…”

“…In the hippocampus, reelin also regulates the developmental switch between different subunits of N-methyl-d-aspartate (22,23), the phosphorylation of the N-methyl-d-aspartate receptor (24), and the development of the hippocampal dendritic arborization (25), and enhances long-term potentiation (26). An impairment in reelin signaling could therefore induce neuroanatomical and/or N-methyl-d-aspartate-regulated glutamate transmission deficits in the hippocampus.…”