October 31, 2021

Preservation of vision after CaMKII-mediated protection of retinal ganglion cells

Author(s):

1 Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2 Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA.
3 Yale College, New Haven, CT 06520, USA.
4 Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5 Laboratory of Molecular Neuroscience, School of Biomedical Sciences and Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
6 Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
7 Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
8 Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA.
9 Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06511, USA.
10 Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Electronic address: bo.chen@mssm.edu.

Retinal ganglion cells (RGCs) are the sole output neurons that transmit visual information from the retina to the brain. Diverse insults and pathological states cause degeneration of RGC somas and axons leading to irreversible vision loss. A fundamental question is whether manipulation of a key regulator of RGC survival can protect RGCs from diverse insults and pathological states, and ultimately preserve vision. Here, we report that CaMKII-CREB signaling is compromised after excitotoxic injury to RGC somas or optic nerve injury to RGC axons, and reactivation of this pathway robustly protects RGCs from both injuries.

CaMKII activity also promotes RGC survival in the normal retina. Further, reactivation of CaMKII protects RGCs in two glaucoma models where RGCs degenerate from elevated intraocular pressure or genetic deficiency. Last, CaMKII reactivation protects long-distance RGC axon projections in vivo and preserves visual function, from the retina to the visual cortex, and visually guided behavior.

PMID: 34297923 PMCID: PMC8530265 (available on 2022-08-05) DOI: 10.1016/j.cell.2021.06.031

Keywords: CREB; CaMKII; RGC; RGC protection; excitotoxicity; glaucoma; optic nerve crush; vision preservation; visual function; visual pathway

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