# Suppression of elevated intracellular Ca2+ as an early intervention to prevent vision loss

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2024 · —

## Abstract

Impaired vision and blindness due to acute and chronic ocular injury and disease, including glaucoma, optic
nerve stroke, and ocular and head trauma have dramatic consequences on the Veteran’s quality of life. Visual
dysfunctions including visual field defects, loss of acuity and blindness are associated with retinal ganglion cell
(RGC) degeneration and apoptosis. The molecular and cellular events mediating RGC degeneration are poorly
understood, and a deeper understanding is required to develop new approaches to protect RGCs after injury.
Early molecular events that impact RGCs after nerve injury and ocular hypertension have been examined;
however, there is little or no quantitative information about acute cellular changes in RGC excitability, Ca2+
permeability, dendrite morphology and synaptic receptor expression. This is in part due to a lack of experimental
approaches that permitted examination of defined RGC types after injury. These experimental limitations can
now be addressed using genetically identified RGCs, including our newly developed model that allows
examination of RGC structure and synaptic receptors immediately after injury.
RGC degeneration is initiated by high intracellular Ca2+ levels followed by a cascade of deleterious cellular events
that end with RGC death. There are multiple cellular sources that mediate an increase in intracellular Ca2+
including calcium-permeable AMPA receptors (CP-AMPARs) that are located at synapses of RGC dendrites.
RGCs rapidly upregulate CP-AMPARs after ocular injury concomitant with an increase of intracellular Ca2+ levels.
Furthermore, RGC survival is enhanced by CP-AMPAR selective antagonists in chronic, ocular hypertensive
models suggesting that suppression of CP-AMPARs is important for protecting injured RGCs.
Studies will test the hypothesis that limiting CP-AMPAR mediated increase of intracellular Ca2 following
optic nerve injury or during early stages of ocular hypertension will preserve RGC function and structure.
Investigations will focus on acute changes of RGCs during the week after optic nerve injury or induction of
elevated intraocular pressure (IOP), and test if RGCs are protected by pharmacological or genetic suppression
of CP-AMPARs. All RGCs express CP-AMPARs, and αRGCs will be used as a model system because their
physiological, structural, and neurochemical properties are well established.
Specific Aim 1 will investigate functional and structural properties of αRGCs following optic nerve injury
or early elevated IOP. Investigations will evaluate αRGC A) physiological properties, including excitability,
synaptic Ca2+ permeability and intracellular Ca2+ levels and B) dendritic field area and complexity, and synaptic
receptor expression. C) Studies will determine if CP-AMPAR expression is regulated by a change in AMPAR
GluA2 subunit level or by the RNA editing enzyme, ADAR2.
Specific Aim 2 will test the effects of pharmacological and genetic suppression of CP-AMPARs on αRGC
function...

## Key facts

- **NIH application ID:** 10795426
- **Project number:** 1I01BX005926-01A2
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** NICHOLAS C. BRECHA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795426

## Citation

> US National Institutes of Health, RePORTER application 10795426, Suppression of elevated intracellular Ca2+ as an early intervention to prevent vision loss (1I01BX005926-01A2). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10795426. Licensed CC0.

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