Transcriptomic changes in retinal ganglion cell types associated with the disruption of cholinergic retinal waves
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Abstract
In the early stages of retinal development, a form of correlated activity known as retinal waves causes periodic depolarizations of immature retinal ganglion cells (RGCs). Retinal waves are crucial for refining visual maps in the brain’s retinofugal targets and for the development of retinal circuits underlying feature detection, such as direction selectivity. Yet, how waves alter gene expression in immature RGCs is poorly understood, particularly at the level of the many distinct types of RGCs that underlie the retina’s ability to encode diverse visual features. We performed single-cell RNA sequencing on RGCs isolated at the end of the first postnatal week from wild-type (WT) mice and β2KO mice, which lack the β2 subunit of the nicotinic acetylcholine receptor, leading to the disruption of cholinergic retinal waves. Statistical comparisons of RGC transcriptomes between the two conditions reveal a weak impact of retinal waves on RGC diversity, indicating that retinal waves do not influence the molecular programs that instruct RGC differentiation and maturation. Although wave-dependent gene expression changes are modest in the global sense, we identified ∼238 genes that are significantly altered in select subsets of RGC types. We focused on one gene, Kcnk9 , which encodes the two-pore domain leak channel potassium channel TASK3. Kcnk9 , which is highly enriched in αRGCs, was strongly downregulated in β2KO. We validated this result using in situ hybridization and performed whole-cell recording to demonstrate a significant decrease in the leak conductance in β2KO RGCs. Our dataset provides a useful resource for identifying potential targets of spontaneous activity-dependent regulation of neurodevelopment in the retina.
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Surprisingly, intersectional analysis revealed that none of these DEGs were wave regulated (Fig. 4C), suggesting that spontaneous activity-mediated DSGC wiring does not occur by modulating cell-intrinsic genetic programs. While this result may also reflect the limited resolution of single-cell sequencing, which captures only about 15% of the cell’s transcriptome (79), it is also possible that retinal waves exerts their influence through post-transcriptional or translational processes in DSGCs (80).
This to me is of the major thought-provoking findings of this paper and suggests that our understanding of how early activity shapes circuit development is worth expanding. I agree that one interpretation of the seemingly wave-independent DEGs could be that there may be post-transcriptional modifications or local protein synthesis at …
Surprisingly, intersectional analysis revealed that none of these DEGs were wave regulated (Fig. 4C), suggesting that spontaneous activity-mediated DSGC wiring does not occur by modulating cell-intrinsic genetic programs. While this result may also reflect the limited resolution of single-cell sequencing, which captures only about 15% of the cell’s transcriptome (79), it is also possible that retinal waves exerts their influence through post-transcriptional or translational processes in DSGCs (80).
This to me is of the major thought-provoking findings of this paper and suggests that our understanding of how early activity shapes circuit development is worth expanding. I agree that one interpretation of the seemingly wave-independent DEGs could be that there may be post-transcriptional modifications or local protein synthesis at synapses. But we also are assuming that major functional changes need to be reflected in transcriptional signatures, and it might be worth exploring the possibility that other mechanisms are at play, such as micro-circuit properties (e.g. synaptic organization), ion channel localization, or something else.
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