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bioRxiv · 10.1101/2024.08.12.607648

Serotonin neuromodulation directs optic nerve regeneration

Saied-Santiago, K.·Baxter, M.·Mathiaparanam, J.·Granato, M.
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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. Summary Statement5-HT1 receptors selectively promote early optic nerve regrowth in zebrafish but are dispensable during development. Serotonin receptor-dependent modulation instructs regenerating optic nerve axons toward the brain in vivo.

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Saied-Santiago, K., Baxter, M., Mathiaparanam, J., Granato, M.. 2024-08-13. Serotonin neuromodulation directs optic nerve regeneration. https://doi.org/10.1101/2024.08.12.607648

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