Astrocyte Metabolic Networks in Neurodegeneration

Abstract

Glaucomatous Optic Neuropathy (glaucoma) challenges retinal ganglion cell axons through sensitivity to intraocular pressure (IOP). Axons rely upon astrocyte energy stores (glycogen) to combat neurodegenerative stress. We find that astrocyte glycogen is not static; rather, metabolites move through gap junctions formed by connexin 43 to supply energy to degenerating tissue. In a unilateral model of glaucoma, such movement occurs through the full unstressed visual projection to the degenerating projection. However, depleting energetic resources affects the function and resilience of the originating tissue. If IOP is elevated in a staggered paradigm wherein resources redistribute before the contralateral eye undergoes elevation, that contralateral eye progresses through neurodegeneration more quickly. Although conditional astrocyte connexin 43 knockout temporarily preserves contralateral function, both projections rapidly degenerate such that after two weeks they exhibit significantly diminished visual function compared to control. Thus, the rapid, widespread remodeling that occurs throughout the astrocyte metabolic network after localized neurodegenerative stress is endogenously protective.