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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alternative Splicing / genetics
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Animals
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Cell Adhesion Molecules, Neuronal / metabolism*
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Cells, Cultured
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Exons / genetics
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Extracellular Matrix Proteins / metabolism*
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Hippocampus / metabolism*
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Hippocampus / ultrastructure
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LDL-Receptor Related Proteins
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Long-Term Potentiation / genetics
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Memory / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Nerve Tissue Proteins / metabolism*
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Neuronal Plasticity / genetics
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Neuronal Plasticity / physiology*
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Organ Culture Techniques
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Phosphorylation
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Protein Isoforms / genetics
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Protein Structure, Tertiary / genetics
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Receptors, Lipoprotein / genetics*
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Receptors, N-Methyl-D-Aspartate / genetics
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Reelin Protein
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Serine Endopeptidases / metabolism*
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Synapses / genetics
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Synapses / metabolism*
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Synaptic Membranes / genetics
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Synaptic Membranes / metabolism
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Synaptic Transmission / genetics
Substances
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Cell Adhesion Molecules, Neuronal
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Extracellular Matrix Proteins
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LDL-Receptor Related Proteins
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Nerve Tissue Proteins
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Protein Isoforms
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Receptors, Lipoprotein
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Receptors, N-Methyl-D-Aspartate
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Reelin Protein
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low density lipoprotein receptor-related protein 8
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Reln protein, mouse
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Serine Endopeptidases