Modulating amacrine cell-derived dopamine signaling promotes optic nerve regeneration and preserves visual function

Sci Adv. 2024 Aug 2;10(31):eado0866. doi: 10.1126/sciadv.ado0866. Epub 2024 Aug 2.

Abstract

As part of the central nervous system, the optic nerve, composed of axons from retinal ganglion cells (RGCs), generally fails to regenerate on its own when injured in adult mammals. An innovative approach to promoting optic nerve regeneration involves manipulating the interactions between amacrine cells (ACs) and RGCs. Here, we identified a unique AC subtype, dopaminergic ACs (DACs), that responded early after optic nerve crush by down-regulating neuronal activity and reducing retinal dopamine (DA) release. Activating DACs or augmenting DA release with levodopa demonstrated neuroprotective effects and modestly enhanced axon regeneration. Within this context, we pinpointed the DA receptor D1 (DRD1) as a critical mediator of DAC-derived DA and showed that RGC-specific Drd1 overexpression effectively overcame subtype-specific barriers to regeneration. This strategy markedly boosted RGC survival and axon regeneration after crush and preserved vision in a glaucoma model. This study unveils the crucial role of DAC-derived DA signaling in optic nerve regeneration, holding promise for therapeutic insights into neural repair.

MeSH terms

  • Amacrine Cells* / metabolism
  • Animals
  • Axons / metabolism
  • Axons / physiology
  • Disease Models, Animal
  • Dopamine* / metabolism
  • Mice
  • Nerve Regeneration* / drug effects
  • Optic Nerve Injuries / drug therapy
  • Optic Nerve Injuries / metabolism
  • Optic Nerve Injuries / pathology
  • Optic Nerve* / metabolism
  • Receptors, Dopamine D1 / metabolism
  • Retinal Ganglion Cells* / drug effects
  • Retinal Ganglion Cells* / metabolism
  • Signal Transduction*
  • Vision, Ocular / physiology

Substances

  • Dopamine
  • Receptors, Dopamine D1