LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation

Neuron. 2015 May 6;86(3):696-710. doi: 10.1016/j.neuron.2015.03.033. Epub 2015 Apr 16.

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.

Publication types

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

MeSH terms

  • Animals
  • Bicuculline / pharmacology
  • CREB-Binding Protein / metabolism
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cells, Cultured
  • Conditioning, Classical / physiology*
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Histone Deacetylases / metabolism
  • Humans
  • LDL-Receptor Related Proteins / genetics
  • LDL-Receptor Related Proteins / metabolism*
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • N-Acetylglucosaminyltransferases / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / physiology*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Signal Transduction / genetics
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics

Substances

  • Cell Adhesion Molecules, Neuronal
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Extracellular Matrix Proteins
  • LDL-Receptor Related Proteins
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • low density lipoprotein receptor-related protein 8
  • CREB-Binding Protein
  • N-Acetylglucosaminyltransferases
  • alpha-1,3-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase I
  • Serine Endopeptidases
  • reelin protein
  • Hdac5 protein, mouse
  • Histone Deacetylases
  • Bicuculline

Associated data

  • GEO/GSE66710