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

Francesca Telese; Qi Ma; Patricia Montilla Perez; Dimple Notani; Soohwan Oh; Wenbo Li; Davide Comoletti; Kenneth A Ohgi; Havilah Taylor; Michael G Rosenfeld

doi:10.1016/j.neuron.2015.03.033

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.

Authors

Affiliations

¹ 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.
² 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.
³ Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ 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.
⁵ 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.
⁶ 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.

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
Reelin Protein
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
Reelin Protein
low density lipoprotein receptor-related protein 8
CREB-Binding Protein
N-Acetylglucosaminyltransferases
alpha-1,3-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase I
RELN protein, human
Reln protein, mouse
Serine Endopeptidases
Hdac5 protein, mouse
Histone Deacetylases
Bicuculline

Associated data

GEO/GSE66710

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding