Targeting Connexin 43 in Retinal Astrocytes Promotes Neuronal Survival in Glaucomatous Injury

Area of Science:

• Neuroscience
• Ophthalmology
• Cell Biology

Background:

• Astrocytes in the retina and optic nerve head are implicated in glaucoma pathogenesis.
• Astrocytes express connexin 43 (Cx43), forming gap junction (GJ) channels and hemichannels.
• The specific role of astrocytic Cx43 in glaucomatous injury remains unclear.

Purpose of the Study:

• To investigate the role of astrocytic Cx43 in glaucoma pathogenesis.
• To assess the impact of Cx43 deletion on retinal ganglion cell (RGC) survival and visual function in mouse models of glaucoma.

Main Methods:

• Utilized mouse models of ocular hypertension (microbead injection) and optic nerve crush (ONC) injury.
• Assessed Cx43 expression, GJ coupling, RGC loss, and visual function (ERG).
• Generated astrocyte-specific Cx43 knockout (Cx43KO) mice to evaluate the effects of Cx43 deletion.

Main Results:

• Cx43 expression and GJ coupling increased in retinal astrocytes with elevated intraocular pressure (IOP) and after ONC injury.
• Astrocyte-specific deletion of Cx43 significantly improved RGC survival (~93%) and preserved visual function in ocular hypertension.
• Cx43 absence increased RGC survival (~48%) in the ONC model.
• Intravitreal injection of the Cx43 hemichannel inhibitor Gap19 improved RGC survival and visual function.

Conclusions:

• Astrocytic Cx43 plays a detrimental role in glaucoma progression.
• Targeting Cx43, particularly hemichannels, shows potential as a therapeutic strategy for glaucoma treatment.
• Further research is warranted to explore the therapeutic efficacy of inhibiting Cx43 hemichannels in glaucoma.