A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke
Open accessAbstract
Stroke causes loss of neurological function. Recovery after stroke is facilitated by forced use of the affected limb and is associated with sprouting of new connections, a process that is sharply confined in the adult brain. We show that ephrin-A5 is induced in reactive astrocytes in periinfarct cortex and is an inhibitor of axonal sprouting and motor recovery in stroke. Blockade of ephrin-A5 signaling using a unique tissue delivery system induces the formation of a new pattern of axonal projections in motor, premotor, and prefrontal circuits and mediates recovery after stroke in the mouse through these new projections. Combined blockade of ephrin-A5 and forced use of the affected limb promote new and surprisingly widespread axonal projections within the entire cortical hemisphere ipsilateral to the stroke. These data indicate that stroke activates a newly described membrane-bound astrocyte growth inhibitor to limit neuroplasticity, activity-dependent axonal sprouting, and recovery in the adult.
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These new connections are causally associated with functional recovery.
“These new connections are causally associated with functional recovery4.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
Stroke induces axonal sprouting and the formation of new connections in peri-infarct cortex that link premotor, motor, somatosensory and association areas.
“Stroke induces axonal sprouting and the formation of new connections in peri-infarct cortex that link premotor, motor, somatosensory and association areas1–4.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
In rodent and primate models of stroke, axonal sprouting and the formation of new connections occurs in motor, somatosensory and premotor areas.
“In rodent and primate models of stroke, axonal sprouting and the formation of new connections occurs in motor, somatosensory and premotor areas1–4.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
GDF10 gain and loss of function was produced directly from the stroke through sustained release via biopolymer hydrogel, which produces release over 2-3 weeks from the stroke site without altering local inflammation, gliosis, neuronal or vascular structure.
“To test this hypothesis, GDF10 gain and loss of function was produced directly from the stroke through sustained release via biopolymer hydrogel, which produces release over 2–3 weeks from the stroke site3,4,28 without altering local inflammation, gliosis, neuronal or vascular structure4.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
Stroke alone modestly but significantly induces axonal sprouting in the motor cortex adjacent to the stroke site compared to normal motor system connections.
“As reported previously3,4,28,29, stroke alone modestly but significantly induces axonal sprouting in the motor cortex adjacent to the stroke site compared to normal motor system connections (Supplementary Fig. 6b).”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
Stroke alone produced increased levels of GFAP, CD31/PECAM and IBA-1, markers for astrocytes, endothelial cells and microglia/macrophages, respectively.
“As previously reported4, stroke alone produced increased levels of GFAP, CD31/PECAM and IBA-1, makers for astrocytes, endothelial cells and microglia/macrophages, respectively (Fig. 5).”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
Nucleotide-modified siRNA delivered directly into the infarct core produces protein knockdown over at least 2 weeks after stroke with GDF10.
“As previously shown in other gene systems3,4, nucleotide-modified siRNA delivered directly into the infarct core produces protein knockdown over at least 2 weeks after stroke with GDF10 (Supplementary Fig. 3a).”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
After stroke, axonal sprouting has been demonstrated in mice, rats and non-human primates.
“After stroke, axonal sprouting has been demonstrated in mice, rats and non-human primates1–4,10,38.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
Stroke normally produces a limited pattern of axonal sprouting from motor or somatosensory cortex posteriorly to areas adjacent to or caudal to the stroke.
“Stroke normally produces a limited pattern of axonal sprouting from motor or somatosensory cortex posteriorly to areas adjacent to or caudal to the stroke2–4,28,29.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
The magnitude of post-stroke axonal sprouting induced by GDF10 exceeds that seen with the blockade of several axonal growth inhibitory systems, such as ephrin-A5 and Nogo/NgR.
“The magnitude of post-stroke axonal sprouting induced by GDF10 exceeds that seen with the blockade of several axonal growth inhibitory systems, such as ephrin-A54 and Nogo/NgR13.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
This anterior projection from motor cortex to premotor cortex is causally associated with functional recovery in this model of stroke.
“This anterior projection from motor cortex to premotor cortex is causally associated with functional recovery in this model of stroke4.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
Sample size for in vivo quantitative cortical mapping studies was estimated from previous publications with similar mechanistic studies.
“Animal number in in vivo quantitative cortical mapping studies utilizes spatial correlation statistics, so sample size was estimated from previous publications with similar mechanistic studies3,4,28,29.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
This experimental design has been validated by other groups conducting similar behavioral or tissue outcomes experiments.
“This experimental design has been validated by other groups conducting similar behavioral4 or tissue outcomes experiments3,4,28,29.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
The biopolymer hydrogel releases both small and large molecules over a 3 week period from the infarct core.
“This biopolymer hydrogel releases both small and large molecules over a 3 week period from the infarct core3,4,29.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [4]
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- Authors
- Overman, J. J., Clarkson, A. N., Wanner, I. B., Overman, W. T., Eckstein, I., Maguire, J. L., Dinov, I. D., Toga, A. W., & Carmichael, S. T.
- Affiliations
- Department of Neurology, David Geffen School of Medicine, and
- University of Otago (NZ)
- University of California, Los Angeles (US)
- Tufts University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-25
- Volume
- 109
- Issue
- 33
- Pages
- E2230-9
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3421211
- OpenAlex
- W2134115573
- Cited by
- 245
- References
- 51
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 11 · 2023: 24 · 2022: 17 · 2021: 22 · 2020: 23 · 2019: 23 · 2018: 17 · 2017: 19 · 2016: 17 · 2015: 19 · 2014: 17 · 2013: 18 · 2012: 3
- FWCI
- 7.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1f31ns061530-01)
- National Institute of Nursing Research (K99NR010797)
- National Institute of Neurological Disorders and Stroke (NS049041, R01NS045729, NS045729, NS061530-02, R01NS049041)
- National Center for Research Resources (RR021813, U54RR021813)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- ephrin-A5, axonal sprouting, stroke recovery, motor recovery, reactive astrocytes, activity-dependent plasticity, neuroplasticity, prefrontal cortex, premotor cortex
- MeSH terms
- Animals, Astrocytes, Axons, Behavior, Animal, Cerebral Cortex, Mice, Inbred C57BL, Motor Activity, Nerve Net, Neuronal Plasticity, Phosphorylation, Staining and Labeling, Signal Transduction, Recovery of Function, Stroke, Ephrin-A5, Mice
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