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Updated: Jun 15, 2025
Minimally-invasive Technique for Injection into Rat Optic Nerve
Published on: May 19, 2015
Serotonin neuromodulation directs optic nerve regeneration
Kristian Saied-Santiago1, Melissa Baxter1, Jaffna Mathiaparanam1
1Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America.
Abstract:
Optic nerve (ON) regeneration in mammalian systems is limited by an overshadowing dominance of inhibitory factors. This has severely hampered the identification of pro-regenerative pathways. Here, we take advantage of the regenerative capacity of larval zebrafish to identify pathways that promote ON regeneration. From a small molecule screen, we identified modulators of serotonin (5-HT) signaling that inhibit ON regeneration. We find several serotonin type-1 receptor genes are expressed in RGC neurons during regeneration and that inhibiting 5-HT1 receptors or components of the 5-HT pathway selectively impedes ON regeneration. We show that 5-HT1 receptor signaling is dispensable during ON development yet is critical for regenerating axons to emerge from the injury site. Blocking 5-HT receptors once ON axons have crossed the chiasm does not inhibit regeneration, suggesting a selective role for 5-HT receptor signaling early during ON regeneration. Finally, we show that agonist-mediated activation of 5-HT1 receptors leads to enhanced and ectopic axonal regrowth. Combined, our results provide evidence for mechanisms through which serotonin-dependent neuromodulation directs ON regeneration in vivo.
Insights
Serotonin (5-HT) signaling inhibits optic nerve regeneration in zebrafish by activating 5-HT1 receptors. Blocking these receptors promotes axonal regrowth, revealing a novel target for enhancing optic nerve repair.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Molecular Biology
Background:
- Mammalian optic nerve regeneration is hindered by inhibitory factors, limiting therapeutic strategies.
- Identifying pro-regenerative pathways is crucial for developing treatments for optic nerve injuries.
Purpose of the Study:
- To identify pathways that promote optic nerve regeneration using larval zebrafish as a model.
- To investigate the role of serotonin (5-HT) signaling in optic nerve regeneration.
Main Methods:
- Conducted a small molecule screen to identify modulators of 5-HT signaling affecting optic nerve regeneration.
- Utilized gene expression analysis to identify serotonin type-1 receptor genes in retinal ganglion cells (RGCs).
- Performed experiments to inhibit 5-HT1 receptors and assess their impact on axonal regeneration.
Main Results:
- Serotonin (5-HT) signaling pathways, specifically 5-HT1 receptors, were identified as inhibitors of optic nerve regeneration.
- Inhibiting 5-HT1 receptors or 5-HT pathway components selectively impeded optic nerve regeneration.
- 5-HT1 receptor signaling is critical for initial axonal emergence from the injury site but not for later regeneration stages.
- Activation of 5-HT1 receptors promoted enhanced and ectopic axonal regrowth.
Conclusions:
- Serotonin-dependent neuromodulation plays a critical role in directing optic nerve regeneration in vivo.
- Targeting 5-HT1 receptor signaling presents a potential therapeutic strategy for promoting optic nerve repair.
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