Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling
Abstract
Communication between glial cells and neurons is emerging as a critical parameter of synaptic function. However, the molecular mechanisms underlying the ability of glial cells to modify synaptic structure and physiology are poorly understood. Here we describe a repulsive interaction that regulates postsynaptic morphology through the EphA4 receptor tyrosine kinase and its ligand ephrin-A3. EphA4 is enriched on dendritic spines of pyramidal neurons in the adult mouse hippocampus, and ephrin-A3 is localized on astrocytic processes that envelop spines. Activation of EphA4 by ephrin-A3 was found to induce spine retraction, whereas inhibiting ephrin/EphA4 interactions distorted spine shape and organization in hippocampal slices. Furthermore, spine irregularities in pyramidal neurons from EphA4 knockout mice and in slices transfected with kinase-inactive EphA4 indicated that ephrin/EphA4 signaling is critical for spine morphology. Thus, our data support a model in which transient interactions between the ephrin-A3 ligand and the EphA4 receptor regulate the structure of excitatory synaptic connections through neuroglial cross-talk.
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EphA4 activation results in reduced spine length and spine density in acute hippocampal slices.
“EphA and EphB have opposing roles with respect to synaptic function; EphA4 is expressed on dendritic spines in pyramidal neurons, and its activation results in reduced spine length as well as spine density in acute hippocampal slices [78].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [78]
EphA4 deletion in mouse brain results in more spines, which are longer and lack organization compared to wild-type.
“To this effect, EphA4 deletion in mouse brain results in more spines, which are longer and lack organization compared to wild-type [78].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [78]
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- Authors
- Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y., & Pasquale, E. B.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Pasquale, Elena B.
- Venue
- Nature Neuroscience
- Published
- 2002-12-23
- Volume
- 6
- Issue
- 2
- Pages
- 153-160
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2056745170
- Cited by
- 516
- References
- 42
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 15 · 2023: 26 · 2022: 13 · 2021: 18 · 2020: 20 · 2019: 13 · 2018: 24 · 2017: 9 · 2016: 23 · 2015: 18 · 2014: 26 · 2013: 28 · 2012: 26
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ey010576-07)
- National Eye Institute (EY10576)
- National Institute of Neurological Disorders and Stroke (NS43029, F32NS043029)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 25938, P01HD025938)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- ephrin-A3, EphA4, dendritic spine morphology, hippocampus, astrocytes, neuroglial interactions, synaptic structure, pyramidal neurons, receptor tyrosine kinase signaling, excitatory synapses
- MeSH terms
- Animals, Astrocytes, Cell Communication, Dendrites, Fluorescent Antibody Technique, Gene Expression Regulation, Hippocampus, Synaptic Transmission, Neuronal Plasticity, Phosphotransferases, Recombinant Fusion Proteins, Synapses, Signal Transduction, Pyramidal Cells, Mice, Knockout, Receptors, Eph Family, Receptor, EphA4, Ephrin-A3, Ephrin-B1, Cell Size, Mice
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