Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning.
Two apolipoprotein E (apoE) receptors, the very low density lipoprotein (VLDL) receptor and apoE receptor 2 (apoER2), are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. In the adult brain, Reelin is expressed by GABA-ergic interneurons, suggesting a potential function as a modulator of neurotransmission. ApoE receptors have been indirectly implicated in memory and neurodegenerative disorders because their ligand, apoE, is genetically associated with Alzheimer disease. We have used knockout mice to investigate the role of Reelin and its receptors in cognition and synaptic plasticity. Mice lacking either the VLDL receptor or the apoER2 show contextual fear conditioning deficits. VLDL receptor-deficient mice also have a moderate defect in long term potentiation (LTP), and apoER2 knockouts have a pronounced one. The perfusion of mouse hippocampal slices with Reelin has no effect on baseline synaptic transmission but significantly enhances LTP in area CA1. This Reelin-dependent augmentation of LTP is abolished in VLDL receptor and apoER2 knockout mice. Our results reveal a role for Reelin in controlling synaptic plasticity in the adult brain and suggest that both of its receptors are necessary for Reelin-dependent enhancement of synaptic transmission in the hippocampus. Thus, the impairment of apoE receptor-dependent neuromodulation may contribute to cognitive impairment and synaptic loss in Alzheimer disease.
Weeber
Edwin J
EJ
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Beffert
Uwe
U
Jones
Chris
C
Christian
Jill M
JM
Forster
Eckart
E
Sweatt
J David
JD
Herz
Joachim
J
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry*; D001921:Brain / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D005239:Fear; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D026502:LDL-Receptor Related Proteins; D007858:Learning; D008024:Ligands; D008079:Lipoproteins, VLDL / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins; D011485:Protein Binding; D020033:Protein Isoforms; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D013569:Synapses / Q000378:metabolism; D013997:Time Factors
D001057:Apolipoproteins E; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D008079:Lipoproteins, VLDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C469363:reelin receptor; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases