**Background:** The vertebrate retina, a thin (~250 µm in humans) central nervous system structure, relies on precise communication between neurons via neurotransmitters and calcium (Ca²⁺) dynamics. Neurotransmitters such as glutamate, GABA, glycine, dopamine, and acetylcholine orchestrate retinal development, physiological function, and disease progression. Despite individual studies, a holistic understanding of their interplay with Ca²⁺ is lacking. This narrative review aims to synthesize current knowledge on these interactions across development, health, and disease, focusing on mouse and primate retinas.
**Methods:** The authors conducted a narrative review of the literature, summarizing findings on retinal structure, synapses (including ribbon and conventional synapses), and development. They systematically examined each neurotransmitter's role in retinal development, normal physiology, and disease, with a dedicated section on its interplay with Ca²⁺. The review integrates data from animal models (e.g., mice, rats, chickens, ferrets, salamanders, goldfish, catfish, turtles, rabbits) and human studies, referencing 279 citations.
**Key Results:**
- **Glutamate:** The primary excitatory neurotransmitter, released by photoreceptors, bipolar cells, and some amacrine cells. During development, glutamatergic retinal waves occur at postnatal days 10–14 in mice, regulated by AMPA receptors and glutamate transporters (EAAT1, EAAT2). NMDA receptors regulate RGC dendrite outgrowth and stabilization. In normal physiology, glutamate acts on ON bipolar cells via mGluR6 (sign-inversing) and OFF bipolar cells via AMPA/kainate receptors (sign-conserving). Dysregulation leads to excitotoxicity in retinal ischemia (elevated extracellular glutamate, Ca²⁺ influx) and glaucoma (reduced GLAST transporter, increased IOP). In diabetic retinopathy, glutamate levels rise, NMDA receptor activation increases intracellular Ca²⁺, and RGC apoptosis occurs.
- **GABA:** The main inhibitory neurotransmitter, released by horizontal and amacrine cells. During development, GABAₐ receptors regulate Ca²⁺ waves in chicken retinas (antagonist increases wave duration). In mice, GAD expression peaks from E17 to P3, then declines after P12. In normal physiology, GABA acts via GABAₐ, GABAᴄ, and GABAₐ receptors, shaping visual responses. In diabetic retinopathy, GABA accumulation increases due to heightened GAD activity and reduced GABA-T activity, with reduced oscillatory potentials on ERG. Retinal ischemia leads to rapid GABA accumulation in glial cells. Antiepileptic drugs like ethosuximide reduce Ca²⁺ currents via T-type channels.
- **Glycine:** Released by AII amacrine cells, crucial for scotopic vision. During development, neonatal glycine receptors (α2 homopentamers) trigger Ca²⁺ influx. In normal physiology, glycine inhibits voltage-gated Ca²⁺ currents via G-protein pathways, reducing signal transmission from bipolar cells to RGCs. ATP suppresses glycine receptor-mediated Ca²⁺ currents in OFF RGCs. cAMP potentiates glycine release via EPAC2 and Ca²⁺ stores in AII amacrine cells. In diabetic retinopathy, glycine supplementation improves RGC nuclear profiles and reduces oxidative stress in rat models.
- **Dopamine:** Released by dopaminergic amacrine cells, detectable from P6 in mice. It modulates circadian rhythms and light adaptation via D₁R (enhances Ca²⁺ currents) and D₂R (reduces dopamine release). D₄ receptors in photoreceptors modulate Ca²⁺ currents. In Parkinson's disease, dopamine deficiency leads to contrast sensitivity loss and color vision deficits. Low dopamine is associated with form-deprivation myopia; bright light exposure prevents myopia in animal models.
- **Acetylcholine (ACh):** Released by starburst amacrine cells (SACs). During development, cholinergic retinal waves occur at P1–10 in mice, propagating Ca²⁺ bursts. Blockade reduces RGC dendritic motility and stratification. In normal physiology, ACh acts via muscarinic (mAChRs) and nicotinic (nAChRs) receptors, enhancing direction selectivity. M₁ mAChRs are crucial for RGC survival. In disease, the ACh agonist pilocarpine constricts the iris via M₃ receptors, reducing IOP in glaucoma, but long-term use causes side effects.
**Clinical Implications:** The review identifies several therapeutic targets: glutamate-release inhibitors for excitotoxicity, ASK1 inhibitors (e.g., selonsertib) for glaucoma, NMDA receptor antagonists (e.g., memantine) for diabetic retinopathy, GABA-transaminase inhibitors (e.g., vigabatrin) for retinal ischemia, glycine supplementation for diabetic retinopathy, and bright light exposure for myopia. However, many drugs have side effects (e.g., vigabatrin causes visual field defects). The authors emphasize the need for further research into Ca²⁺-dependent mechanisms of these neurotransmitters, particularly for glycine, dopamine, and ACh, to develop safer, more effective therapies.