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Editors Selection IGR 17-4

Basic Science: Neuroprotection 1

Comment by Adriana DiPolo on:

67595 Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma, Williams PA; Tribble JR; Pepper KW et al., Molecular Neurodegeneration, 2016; 11: 26

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Retinal ganglion cells (RGCs) are highly compartmentalized neurons: they are endowed with dendrites, the specialized processes responsible for collecting and processing information within the retina, and with long-projecting axons that reach visual targets in the brain. RGC dendrites receive synaptic inputs from bipolar and amacrine cells, thus playing a crucial role in cell-to-cell communication and flow of visual information. It is increasingly recognized that pathological changes in RGC dendrites occur early in glaucoma and precede overt soma or axonal loss. However, the precise mechanisms triggering RGC dendritic deficits remain poorly understood.

This is an interesting and valuable study that identifies the neuroinflammatory mediator C1q as an important regulator of early dendritic and synaptic deficits in glaucoma

An intriguing observation in recent years is that the classical complement cascade, which typically plays a role during inflammation, can also contribute to the selective pruning of dendrites and synapses during central nervous system development. In this new study, Williams and colleagues tested the hypothesis that C1q, a component of the complement system, plays a role in early synapse loss and dendritic atrophy in glaucoma. The authors demonstrate that synaptic atrophy occurs at early disease stages using two glaucoma models: DBA/2J mice and rats subjected to ocular hypertension by injection of magnetic microbeads. Importantly, C1q inhibition by genetic ablation or with pharmacological blockers preserved RGC dendrites and their synapses. These data support a role for early C1q-mediated RGC dendritic pruning and synapse loss in glaucoma.

This study was carefully designed and rigorously executed. The observation that C1q contributes to dendritic alterations in different glaucoma models and species lends credibility to the findings. The authors recognize the possibility of potential regional bias using the DiOlistic labeling of dendritic arbors, a method that involves delivery of dye-coated particles to flat-mounted retinas using a gene gun system. In their favor, no apparent loss of selective RGC types was found. It will be of interest, nonetheless, to reproduce the current findings using novel genetic tools that allow visualization of RGC subtypes. Given the impressive protective effect of C1q inhibition on RGC dendritic structure, it will be helpful to evaluate the implications of C1q blockade on RGC function. All in all, this is an interesting and valuable study that identifies the neuro-inflammatory mediator C1q as an important regulator of early dendritic and synaptic deficits in glaucoma.

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