Astrocytes Try to Rescue Fellow Eye’s Optic Nerve

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As storehouses for glycogen, astrocytes are known to nourish optic nerves by funneling large amounts of metabolic energy (for example, lactose) to the retinal ganglion cell axons, which transfer visual signals to the brain. But new research has revealed that the as­trocytes in a healthy optic nerve play a key role in responding to neurodegen­erative signals from the contralateral, glaucomatous eye: The astrocytes begin donating some of the healthy optic nerve’s metabolic resources to the nerve from the eye with glaucoma.¹

Ironically, this redistribution of available energy weakens the healthy optic nerve and may explain why glaucoma that begins in one eye often “spreads” to the other eye, said senior author David J. Calkins, PhD, at the Vanderbilt Vision Research Center in Nashville, Tennessee.

ENERGY TRANSFER. Astrocytes (purple) in the mouse retina interconnect via gap junctions to form a plexus that covers retinal ganglion cells and their axons (green), which form the optic nerve to the brain.

Novel finding. “This is the first time anyone has demonstrated the sharing of energy resources between the two eyes and nerves,” Dr. Calkins said. “But unfortunately, because these resources are limited, the nerve that donates the resources becomes more susceptible to intraocular pressure–related stress in glaucoma.” Thus, he said, “Over time the pathology in the two optic projec­tions to the brain equilibrates, endan­gering both optic nerves.”

Murine model. Working with a mouse model of glaucoma, the scien­tists found that astrocytes used gap junctions to transport metabolites along the long distance from one optic nerve, through the optic chasm, to the other optic nerve. (In a human, this would correspond to several centime­ters, Dr. Calkins said.)

The movement was facilitated by connexin 43 (Cx43), an essential pro­tein, the researchers reported. In the ab­sence of Cx43, this protective response to oxidative and metabolic stress did not occur.

Dr. Calkins said the group’s next step is to build a viral vector modified to upregulate the astrocytes’ capacity to store glycogen and exchange energy. “Basically what we’re trying to do is build and bootstrap energy depots large enough to keep both optic nerves healthy,” he said.

A role in other neurodegenerative diseases? It is possible that a similar astrocyte-mediated rescue mechanism is at work in other neurodegenerative conditions, Dr. Calkins said. For in­stance, in patients with Leber heredi­tary optic neuropathy who have under­gone gene therapy and in patients with the Argus II retinal implant (Second Sight), there have been reports that the untreated eyes show unexplained visual improvement, he said. And Alzheimer disease lesions in one brain hemisphere commonly appear in the other hemi­sphere over time, he said.

Call for research. “I think we need to put more research into understand­ing how the two optic projections can talk to one another,” Dr. Calkins said. “The gap junctions between astrocytes are large enough to pass different kinds of molecules.” He added, “This is exciting because it opens up entire new avenues for understanding how pathology spreads between the two eyes.”

—Linda Roach

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1 Cooper ML et al. Proc Natl Acad Sci U S A. 2020;117(31):18810-18821.

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Relevant financial disclosures—Dr. Calkins: None.

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