Reelin regulates the maturation of dendritic spines, synaptogenesis and glial ensheathment of newborn granule cells
Open accessAbstract
The Reelin pathway is essential for both neural migration and for the development and maturation of synaptic connections. However, its role in adult synaptic formation and remodeling is still being investigated. Here, we investigated the impact of the Reelin/Dab1 pathway on the synaptogenesis of newborn granule cells (GCs) in the young-adult mouse hippocampus. We show that neither Reelin overexpression nor the inactivation of its intracellular adapter, Dab1, substantially alters dendritic spine numbers in these neurons. In contrast, 3D-electron microscopy (focused ion beam milling/scanning electron microscope) revealed that dysregulation of the Reelin/Dab1 pathway leads to both transient and permanent changes in the types and morphology of dendritic spines, mainly altering mushroom, filopodial, and branched GC spines. We also found that the Reelin/Dab1 pathway controls synaptic configuration of presynaptic boutons in the dentate gyrus, with its dysregulation leading to a substantial decrease in multi-synaptic bouton innervation. Lastly, we show that the Reelin/Dab1 pathway controls astroglial ensheathment of synapses. Thus, the Reelin pathway is a key regulator of adult-generated GC integration, by controlling dendritic spine types and shapes, their synaptic innervation patterns, and glial ensheathment. These findings may help to better understanding of hippocampal circuit alterations in neurological disorders in which the Reelin pathway is implicated. The extracellular protein Reelin has an important role in neurological diseases, including epilepsy, Alzheimer's disease and psychiatric diseases, targeting hippocampal circuits. Here we address the role of Reelin in the development of synaptic contacts in adult-generated granule cells (GCs), a neuronal population that is crucial for learning and memory and implicated in neurological and psychiatric diseases. We found that the Reelin pathway controls the shapes, sizes, and types of dendritic spines, the complexity of multisynaptic innervations and the degree of the perisynaptic astroglial ensheathment that controls synaptic homeostasis. These findings show a pivotal role of Reelin in GC synaptogenesis and provide a foundation for structural circuit alterations caused by Reelin deregulation that may occur in neurological and psychiatric disorders.
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ApoER2 mediates Reelin signaling to enhance learning and memory in mice.
“Since loss of ApoER2 impairs LTP, and since ApoER2 mediates Reelin signaling to enhance learning and memory in mice (Bosch et al., 2016; Niu et al., 2008; Rogers et al., 2011), it has been suggested that increased ApoER2 expression would be beneficial.”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Bosch et al., 2016
The Introduction states that ApoER2 mediates Reelin signaling. The Discussion reports changes in mouse synapses and suggests that altered Reelin signaling may affect rhythms important for learning and memory, but it does not show that ApoER2-mediated signaling enhances learning or memory in mice. (LLM, conf=0.88)
Experimental — accuracy not yet measuredActin polymerization and dendritic spine growth exhibit a net increase in the presence of Reelin, and mice that overexpress Reelin have higher spine density and increased spine complexity.
“actin polymerization and dendritic spine growth exhibit a net increase in the presence of Reelin, and mice that overexpress Reelin have higher spine density and increased spine complexity [64, 65].”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [65]
The reelin pathway participates in the integration of adult-born neurons into the hippocampal circuitry by regulating spine morphology, spine type, and the number of synaptic connections on new granule neurons as well as the degree of perisynaptic astroglial ensheathment of new granule neuron synapses.
“The reelin pathway also participates in the integration of adult-born neurons into the hippocampal circuitry by regulating spine morphology, spine type, and the number of synaptic connections on new granule neurons as well as the degree of perisynaptic astroglial ensheathment of new granule neuron synapses (Bosch et al., 2016).”
From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Bosch et al., 2016
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Reelin gene variants and risk of autism spectrum disorders: An integrated meta‐analysis
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Aberrant Neurogenesis After Stroke
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“As a result, actin polymerization and dendritic spine growth exhibit a net increase in the presence of Reelin, and mice that overexpress Reelin have higher spine density and increased spine complexity [64, 65].”
BackgroundLiu, Y., Ouyang, P., Zheng, Y., Mi, L., Zhao, J., Ning, Y., & Guo, W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.664535 · Cited by 129 · see citing works
Imaging Synaptic Density: The Next Holy Grail of Neuroscience?
Serrano, M. E., Kim, E., Petrinovic, M. M., Turkheimer, F., & Cash, D. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.796129 · Cited by 67 · see citing works
Gao, J., Marosi, M., Choi, J., Achiro, J. M., Kim, S., Li, S., Otis, K., Martin, K. C., Portera-Cailliau, C., & Tontonoz, P. (2017) · eLife · doi:10.7554/elife.29178 · Cited by 30 · see citing works
The role of reelin in the pathological mechanism of depression from clinical to rodents
Jin, K., Zhang, S., Jiang, C., Liu, R., Chen, B., Zhao, H., Zhang, Q., Shen, Z., Xu, P., Hu, X., et al. (2022) · Psychiatry Research · doi:10.1016/j.psychres.2022.114838 · Cited by 13 · see citing works
- Authors
- Bosch, C., Masachs, N., Exposito-Alonso, D., Martínez, A., Teixeira, C. M., Fernaud, I., Pujadas, L., Ulloa, F., Comella, J. X., DeFelipe, J., Merchán-Pérez, A., & Soriano, E.
- Affiliations
- Instituto de Salud Carlos III (ES)
- Parc Científic de Barcelona (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Universitat Autònoma de Barcelona (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Bosch, Carles
- ORCID
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-09-13
- Volume
- 26
- Issue
- 11
- Pages
- 4282-4298
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC5066826
- OpenAlex
- W2481871900
- Cited by
- 70
- References
- 132
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 6 · 2020: 14 · 2019: 5 · 2018: 10 · 2017: 5
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cerebral Cortex (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Spanish MINECO (BFU 2008-03980, SAF 2013-42445R, SAF 2013-2010-19930, 13-00027, SAF 2015-66603-P)
- CIBERNED
- Cajal Blue Brain Project, Spanish partner of the Blue Brain Project
- European Union Seventh Framework Programme (FP7/2007-2013, 604102)
- Human Brain Project
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- reelin, Dab1, dendritic spine maturation, synaptogenesis, hippocampus, dentate gyrus, synaptic homeostasis, adult neurogenesis
- MeSH terms
- Disks Large Homolog 4 Protein, Reelin Protein, Animals, Brain, Cell Differentiation, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Neuroglia, Neurons, Serine Endopeptidases, Synapses, Transduction, Genetic, Signal Transduction, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Microscopy, Confocal, Imaging, Three-Dimensional, Dendritic Spines, Green Fluorescent Proteins, Mice, Neurogenesis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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