Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway
Open accessAbstract
Defective brain extracellular matrix (ECM) is a factor of vulnerability in various psychiatric diseases such as schizophrenia, depression and autism. The glycoprotein reelin is an essential building block of the brain ECM that modulates neuronal development and participates to the functions of adult central synapses. The reelin gene (RELN) is a strong candidate in psychiatric diseases of early onset, but its synaptic and behavioral functions in juvenile brain circuits remain unresolved. Here, we found that in juvenile reelin-haploinsufficient heterozygous reeler mice (HRM), abnormal fear memory erasure is concomitant to reduced dendritic spine density and anomalous long-term potentiation in the prefrontal cortex. In juvenile HRM, a single in vivo injection with ketamine or Ro25-6981 to inhibit GluN2B-N-methyl-D-aspartate receptors (NMDARs) restored normal spine density, synaptic plasticity and converted fear memory to an erasure-resilient state typical of adult rodents. The functional and behavioral rescue by ketamine was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin pathway. Finally, we show that fear memory erasure persists until adolescence in HRM and that a single exposure to ketamine during the juvenile period reinstates normal fear memory in adolescent mice. Our results show that reelin is essential for successful structural, functional and behavioral development of juvenile prefrontal circuits and that this developmental period provides a critical window for therapeutic rehabilitation with GluN2B-NMDAR antagonists.
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HRM mice have reduced short-term contextual fear learning and deficient long-term association of both forms of fear memory.
“Reelin's role in fear memory is further supported by the observations that HRM mice have reduced short-term contextual fear learning (32) and deficient longterm association of both forms of fear memory (33).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [33]
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- Authors
- Iafrati, J., Orejarena, M. J., Lassalle, O., Bouamrane, L., & Chavis, P.
- Affiliations
- Inserm (FR)
- Corresponding author
- Chavis, P
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2013-06-11
- Volume
- 19
- Issue
- 4
- Pages
- 417-426
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3965840
- OpenAlex
- W1969861119
- Cited by
- 132
- References
- 66
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 4 · 2022: 8 · 2021: 15 · 2020: 11 · 2019: 6 · 2018: 10 · 2017: 10 · 2016: 26 · 2015: 8 · 2014: 16 · 2013: 3
- FWCI
- 8.67
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-10-22)
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- reelin, extracellular matrix, prefrontal cortex development, mTOR signaling, dendritic spine density, long-term potentiation, ketamine, Ro 25-6981, rapamycin, reeler mice, schizophrenia, depression, autism spectrum disorder, synaptic plasticity
- MeSH terms
- Reelin Protein, Analysis of Variance, Animals, Animals, Newborn, Conditioning, Classical, Dose-Response Relationship, Drug, Extinction, Psychological, Fear, Female, Ketamine, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Phenols, Piperidines, Serine Endopeptidases, Signal Transduction, Cell Adhesion Molecules, Neuronal, Receptors, N-Methyl-D-Aspartate, Extracellular Matrix Proteins, Prefrontal Cortex, Long-Term Potentiation, Mice, Knockout, Patch-Clamp Techniques, Excitatory Amino Acid Agents, Sirolimus, Dendritic Spines, Mice, TOR Serine-Threonine Kinases, In Vitro Techniques
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