Developmental synchrony of retinal waves, apoptosis, and angiogenesis in postnatal retina

Postnatal mouse retinal development involves a complex interplay of spontaneous neural activity, vascular plexus growth, and programmed cell death. Though these processes appear to interact at a general level, the precise mechanisms connecting them have not been clearly understood. Researchers employed advanced imaging techniques, such as wide-field calcium imaging and high-density multielectrode array recordings, along with single-cell RNA sequencing and immunohistochemistry, to examine the development of retinal waves, vascular growth, Heme oxygenase-1 (Hmox1) expressing microglia, apoptotic cell markers, and unique auto-fluorescent cluster complexes (ACCs).

A distinctive pattern was observed, wherein retinal waves onsets, vascular development, ACCs, and apoptotic cells escalated concurrently during stage II retinal development. Apoptotic cells are known to increase functional pannexin-1 (PANX-1) hemichannels, which release purinergic molecules acting as 'eat me' signals for neighboring microglia.

When the PANX-1 hemichannel function is inhibited with the drug probenecid, the frequency and strength of spontaneous retinal waves significantly decrease, indicating that apoptotic cells may indeed be a trigger for these waves. The study further suggests that these waves are first initiated in small, hyperactive regions by apoptotic retinal ganglion cells (RGCs), followed by their release of purinergic molecules via PANX-1 hemichannels.

This surge of activity leads to hypoxic conditions and high extracellular ATP concentrations, promoting angiogenesis. Once blood vessels appear at a specific hotspot, ATP release activates Hmox1-positive microglia, which engulf the dying RGCs, forming the distinctive ACCs. This research presents a plausible unified mechanism linking early neural activity, programmed cell death, and angiogenesis in the mammalian retina.