LRP8-Reelin-regulated neuronal enhancer signature underlying learning and memory formation
Open accessAbstract
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.
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ApoER2-ICD can translocate to the nucleus and alter transcription of genes including inhibition of Reelin transcription.
“the ApoER2-ICD can translocate to the nucleus and alter transcription of genes including inhibition of Reelin transcription (38,39).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [39]
Both ApoER2 cleavage fragments are negative feedback regulators of the Reelin signal.
“Both ApoER2 cleavage fragments are negative feedback regulators of the Reelin signal.”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [39]
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References 94 · Cited by 166
- Authors
- Telese, F., Ma, Q., Perez, P. M., Notani, D., Oh, S., Li, W., Comoletti, D., Ohgi, K. A., Taylor, H., & Rosenfeld, M. G.
- Affiliations
- Howard Hughes Medical Institute (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Telese, Francesca
- Rosenfeld, Michael G.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 86
- Issue
- 3
- Pages
- 696-710
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4486257
- OpenAlex
- W2066901047
- Cited by
- 166
- References
- 94
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 19 · 2023: 15 · 2022: 14 · 2021: 9 · 2020: 19 · 2019: 16 · 2018: 8 · 2017: 15 · 2016: 17 · 2015: 8
- FWCI
- 7.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (R01HL065445, HL065445)
- National Cancer Institute (CA173903, R01CA173903)
- National Institute of General Medical Sciences (R01GM104459, GM104459)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK039949, DK 039949, DK018477, R37DK039949, R01DK018477)
- National Institute of Neurological Disorders and Stroke (R01NS034934, NS034934)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- LRP8, Reelin signaling, synaptic plasticity, gamma-secretase cleavage, transcriptional regulation, mental illness
- MeSH terms
- Reelin Protein, Animals, Bicuculline, Cells, Cultured, Conditioning, Classical, Embryo, Mammalian, Enzyme Inhibitors, Histone Deacetylases, Humans, Memory, Mice, Inbred C57BL, Mice, Transgenic, Models, Molecular, Nerve Tissue Proteins, Synaptic Transmission, Neurons, Serine Endopeptidases, Signal Transduction, Cell Adhesion Molecules, Neuronal, Receptors, N-Methyl-D-Aspartate, Extracellular Matrix Proteins, N-Acetylglucosaminyltransferases, Excitatory Amino Acid Antagonists, LDL-Receptor Related Proteins, CREB-Binding Protein, Mice
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