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

• DOI: 10.1016/j.neuron.2005.07.007
• Publication Date: 2005-08-18T11:36:55Z
• Authors: Uwe Beffert; Edwin J. Weeber; Andre Durudas; Shenfeng Qiu; Irene Masiulis; J. David Sweatt; Wei-Ping Li; Giselind Adelmann; Michael Frotscher; Robert E. Hammer; Joachim Herz
• Keywords: 0301 basic medicine; Extracellular Matrix Proteins; Neuronal Plasticity; Neuroscience(all); Cell Adhesion Molecules, Neuronal; Long-Term Potentiation; Mice, Transgenic; Nerve Tissue Proteins; Exons; Hippocampus; Protein Structure, Tertiary; Mice, Inbred C57BL; Alternative Splicing; Mice; 03 medical and health sciences; Organ Culture Techniques; Memory; Animals; Protein Isoforms; Phosphorylation; Cells, Cultured; LDL-Receptor Related Proteins; Receptors, Lipoprotein

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.