Piezo1 and Piezo2 channels in retinal ganglion cells and the impact of Piezo1 stimulation on light-dependent neural activity
Authors: Sripinun Puttipong , See Lily P. , Nikonov Sergei , Chavali Venkata Ramana Murthy , Vrathasha Vrathasha , He Jie , O’Brien Joan M. , Xia Jingsheng , Lu Wennan , Mitchell Claire H. 
Published: June 2024

AbstractPiezo channels are associated with neuropathology in diseases like traumatic brain injury and glaucoma, but pathways linking tissue stretch to aberrant neural signaling remain unclear. The present study demonstrates that Piezo1 activation increases action potential frequency in response to light and the spontaneous dark signal from mouse retinal explants. Piezo1 stimulation was sufficient to increase cytoplasmic Ca2+in soma and neurites, while stretch increased spiking activity in current clamp recordings from of isolated retinal ganglion cells (RGCs). Axon-marker beta-tubulin III colocalized with both Piezo1 and Piezo2 protein in the mouse optic nerve head, while RGC nuclear marker BRN3A colocalized with Piezo channels in the soma. Piezo1 was also present on GFAP-positive regions in the optic nerve head and colocalized with glutamine synthetase in the nerve fiber layer, suggesting expression in optic nerve head astrocytes and Müller glia end feet, respectively. Human RGCs from induced pluripotent stem cells also expressed Piezo1 and Piezo2 in soma and axons, while staining patterns in rats resembled those in mice. mRNA message forPiezo1was greatest in the RPE/choroid tissue, whilePiezo2levels were highest in the optic nerve, with both channels also expressed in the retina. Increased expression ofPiezo1andPiezo2occurred both 1 and 10 days after a single stretchin vivo;this increase suggests a potential role in rising sensitivity to repeated nerve stretch. In summary, Piezo1 and Piezo2 were detected in the soma and axons of RGCs, and stimulation affected the light-dependent output of RGCs. The rise in RGCs excitability induced by Piezo stimulation may have parallels to the early disease progression in models of glaucoma and other retinal degenerations.HighlightsActivation of Piezo1 excites retinal ganglion cells, paralleling the early neurodegenerative progression in glaucoma mouse models and retinal degeneration.Piezo1 and Piezo2 were expressed in axons and soma of retinal ganglion cells in mice, rats, and human iPSC-RGCs.Functional assays confirmed Piezo1 in soma and neurites of neurons.Sustained elevation ofPiezo1andPiezo2occurred after a single transient stretch may enhance damage from repeated traumatic nerve injury.Abstract FigureGraphical abstractPiezo1 and Piezo2 channels in retinal ganglion cells and the impact of Piezo1 stimulation on light-dependent neural activity. Puttipong Sripinun, Lily P. See, Sergei Nikonov, Venkata Ramana Murthy Chavali, Vrathasha Vrathasha, Jie He, Joan M. O’Brien, Jingsheng Xia, Wennan Lu, Claire H. Mitchell*. Activation of Piezo channels through mechanical or pharmacological stimulation leads to an influx of Ca2+and other cations into RGCs, depolarizing the membrane and increasing the action potential frequency to modulate the visual signal. Created with Biorender.com