# Modulation of GABAergic System in a Chicken Retinal Ischemic Model: The Role of Chloride Cotransporters

## TL;DR

This study explores how the GABAergic system and chloride transporters contribute to retinal damage during ischemia in a chicken model, suggesting potential therapeutic strategies.

## Contribution

The study identifies the role of GABAergic system modulation and chloride cotransporters in retinal ischemia and proposes pharmacological interventions for neuroprotection.

## Key findings

- OGD-induced retinal damage is linked to reduced GABA levels and increased NKCC1 levels.
- Pharmacological agents like picrotoxin and bumetanide show neuroprotective effects by modulating GABAergic activity.
- Ischemia alters chloride homeostasis, leading to cell depolarization and increased cell death.

## Abstract

Retinal ischemia is a significant pathological condition that contributes to visual impairment and neuronal cell death in various retinopathies. Evidence suggests that GABA release during ischemic events may exhibit neuroprotective properties, but conflicting findings highlight a potential shift in its effects due to altered chloride ion homeostasis. This study aimed to investigate the role of the GABAergic system in retinal ischemia, focusing on the temporal dynamics of GABA release and its impact on retinal damage. We hypothesized that ischemia‐induced changes in GABA transport and chloride ion equilibrium contribute to neuronal damage, which can be mitigated by modulating GABAergic activity. Using an ex vivo chick retina model subjected to oxygen and glucose deprivation (OGD), during different times, we assessed morphological changes, cell death, GABA levels, transporter activity, and the levels of chloride cotransporters NKCC1 and KCC2. Pharmacological interventions, including picrotoxin and bumetanide, were used to evaluate neuroprotective effects. Our results revealed that OGD‐induced significant morphological changes and cell death in the retina. GABA levels were reduced in a GAT‐1‐dependent manner, while picrotoxin and bumetanide demonstrated neuroprotective effects by mitigating retinal swelling and modulating the GABAergic system. Notably, OGD increased NKCC1 content, but not KCC2 levels, indicating a disruption in chloride homeostasis. These findings suggest that ischemia‐induced alterations in GABAergic activity and chloride transport contribute to retinal damage. Targeting these pathways with pharmacological agents, such as bumetanide, may offer therapeutic strategies for mitigating ischemic retinal injury. Further research is recommended to explore the clinical applicability of these findings in the ischemic retina.

Oxygen–glucose deprivation (OGD) promotes GABA release and increases NKCC1 levels, which change the electrochemical chloride gradient. In these circumstances, activation of ionotropic GABA receptors would lead to cell depolarization. Thus, in the early stages of ischemia, GABA intensifies glutamate excitotoxicity by an alteration in chloride transporters, worsening cell death.