Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2.
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.
Beffert
Uwe
U
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Weeber
Edwin J
EJ
Durudas
Andre
A
Qiu
Shenfeng
S
Masiulis
Irene
I
Sweatt
J David
JD
Li
Wei-Ping
WP
Adelmann
Giselind
G
Frotscher
Michael
M
Hammer
Robert E
RE
Herz
Joachim
J
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002478:Cells, Cultured; D005091:Exons / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D026502:LDL-Receptor Related Proteins; D017774:Long-Term Potentiation / Q000235:genetics; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D018110:Receptors, Lipoprotein; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases