Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature

Abstract

One important facet of glaucoma pathophysiology is axonal damage, which ultimately disrupts the connection between the retina and its postsynaptic brain targets. The concurrent loss of retrograde support interferes with the functionality and survival of the retinal ganglion cells (RGCs). Previous research has shown that stimulation of neuronal activity in a primary retinal target area—i.e., the superior colliculus—promotes RGC survival in an acute mouse model of glaucoma. To build further on this observation, we applied repeated chemogenetics in the superior colliculus of a more chronic murine glaucoma model—i.e., the microbead occlusion model—and performed bulk RNA sequencing on collicular lysates and isolated RGCs. Our study revealed that chronic target stimulation upon glaucomatous injury phenocopies the a priori expected molecular response: growth factors were pinpointed as essential transcriptional regulators both in the locally stimulated tissue and in distant, unstimulated RGCs. Strikingly, and although the RGC transcriptome revealed a partial reversal of the glaucomatous signature and an enrichment of pro-survival signaling pathways, functional rescue of injured RGCs was not achieved. By postulating various explanations for the lack of RGC neuroprotection, we aim to warrant researchers and drug developers for the complexity of chronic neuromodulation and growth factor signaling.

Keywords

• chemogenetics
• DREADDs
• glaucoma
• retinal ganglion cells
• superior colliculus
• postsynaptic target area