Modulation of Synaptic Plasticity and Memory by Reelin Involves Differential Splicing of the Lipoprotein Receptor Apoer2

Abstract

Apolipoprotein E receptor 2 (Apoer2), a member of the LDL receptor gene family, and its ligand Reelin control neuronal migration during brain development. Apoer2 is also essential for induction of long-term potentiation (LTP) in the adult brain. Here we show that Apoer2 is present in the postsynaptic densities of excitatory synapses where it forms a functional complex with NMDA receptors. Reelin signaling through Apoer2 markedly enhances LTP through a mechanism that requires the presence of amino acids encoded by an exon in the intracellular domain of Apoer2. This exon is alternatively spliced in an activity-dependent manner and is required for Reelin-induced tyrosine phosphorylation of NMDA receptor subunits. Mice constitutively lacking the exon perform poorly in learning and memory tasks. Thus, alternative splicing of Apoer2, a novel component of the NMDA receptor complex, controls the modulation of NMDA receptor activity, synaptic neurotransmission, and memory by Reelin.

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

“…These findings explain the profound effect of Reelin on glutamatergic neurotransmission and synaptic plasticity ex corpore (Weeber et al 2002;Beffert et al 2005;Beffert et al 2006b;Qiu et al 2006;Campo et al 2009) and in vivo (Pujadas et al 2010) (E Weeber, pers. comm.).…”

“…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.…”

“…However, they harbor a variety of short conserved sequence stretches, such as the tetra-amino acid NPxY motif, which serve as docking sites for a wide array of cytoplasmic adaptor and scaffolding proteins (Trommsdorff et al 1998;Gotthardt et al 2000;Beffert et al 2005;Hoe et al 2006a;Hoe et al 2006b). The receptors can also interact as coreceptors through their extracellular domains with other types of signaling proteins and modules, and thereby modulate their intrinsic activity (Boucher et al 2002;Loukinova et al 2002;Huang et al 2003;Lillis et al 2008;Zurhove et al 2008), including that of the N-methyl-D-aspartate (NMDA) receptor Beffert et al 2005;Hoe et al 2006b). …”

“…Increased tyrosine phosphorylation of the NMDA receptor increases ion gating and reduces its endocytosis, thereby increasing NMDA receptor activity overall (Salter and Kalia 2004;Snyder et al 2005). Intriguingly, differential splicing of this exon is regulated in a circadian, activitydriven manner , suggesting that periodic variation of NMDA receptor activity by Reelin is physiologically significant for synapse function, learning, and memory Weeber et al 2002;Beffert et al 2005;D'Arcangelo 2005;Beffert et al 2006b;Pujadas et al 2010).…”

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

“…39 Reelin serves a dual purpose in the mammalian brain: it is crucial to the correct cytoarchitecture of laminated structures during embryonic development 18,40 and modulates dendritic growth and synaptic plasticity at post-natal and adult stages. 41,42 These activities are, at least in part, mediated by binding to apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), [43][44][45] resulting in phosphorylation of the intracellular adaptor protein protein disabled homolog 1 (DAB1). [46][47][48] Phosphorylated DAB1 activates several different signaling pathways involved in formation and plasticity of neuronal networks (for review, see ref.…”