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

Neuron. 2005 Aug 18;47(4):567-79. doi: 10.1016/j.neuron.2005.07.007.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cells, Cultured
  • Exons / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Hippocampus / metabolism*
  • Hippocampus / ultrastructure
  • LDL-Receptor Related Proteins
  • Long-Term Potentiation / genetics
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism*
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*
  • Organ Culture Techniques
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Structure, Tertiary / genetics
  • Receptors, Lipoprotein / genetics*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Serine Endopeptidases / metabolism*
  • Synapses / genetics
  • Synapses / metabolism*
  • Synaptic Membranes / genetics
  • Synaptic Membranes / metabolism
  • Synaptic Transmission / genetics

Substances

  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • LDL-Receptor Related Proteins
  • Nerve Tissue Proteins
  • Protein Isoforms
  • Receptors, Lipoprotein
  • Receptors, N-Methyl-D-Aspartate
  • low density lipoprotein receptor-related protein 8
  • Serine Endopeptidases
  • reelin protein