title: LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.
abstract: One of the exceptional properties of the brain is its ability to acquire new knowledge through learning and to store that information through memory. The epigenetic mechanisms linking changes in neuronal transcriptional programs to behavioral plasticity remain largely unknown. Here, we identify the epigenetic signature of the neuronal enhancers required for transcriptional regulation of synaptic plasticity genes during memory formation, linking this to Reelin signaling. The binding of Reelin to its receptor, LRP8, triggers activation of this cohort of LRP8-Reelin-regulated neuronal (LRN) enhancers that serve as the ultimate convergence point of a novel synapse-to-nucleus pathway. Reelin simultaneously regulates NMDA-receptor transmission, which reciprocally permits the required γ-secretase-dependent cleavage of LRP8, revealing an unprecedented role for its intracellular domain in the regulation of synaptically generated signals. These results uncover an in vivo enhancer code serving as a critical molecular component of cognition and relevant to psychiatric disorders linked to defects in Reelin signaling.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ftelese@ucsd.edu.
authors.forename: Francesca
authors.initials: F
authors.lastname: Telese
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Bioinformatis and System Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Patricia Montilla
authors.initials: PM
authors.lastname: Perez
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Dimple
authors.initials: D
authors.lastname: Notani
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Soohwan
authors.initials: S
authors.lastname: Oh
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Li
authors.affiliation: Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Comoletti
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Ohgi
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Havilah
authors.initials: H
authors.lastname: Taylor
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: mrosenfeld@ucsd.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003214:Conditioning, Classical / Q000502:physiology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; D050882:CREB-Binding Protein; D017351:N-Acetylglucosaminyltransferases; C024850:alpha-1,3-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase I; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D001640:Bicuculline