Overexpression or Activation of Potassium Channel TASK-3 Protects Retinal Ganglion Cells and Restores Visual Function in Optic Nerve Crush

Purpose: This study explored in a mouse model whether activation or upregulation of the two-pore domain potassium channel tandem pore domain acid-sensitive potassium channel 3 (TASK-3) in retinal ganglion cells (RGCs) could protect RGCs and reverse the vision loss arising through optic nerve injury. Methods: TASK-3 activity was assessed using patch-clamp electrophysiology. The optic nerve of each mouse was crushed, and the selective TASK-3 agonist CHET3 was applied to the surface of the eye once daily for 1 week or TASK-3 was overexpressed specifically in RGCs through infection with recombinant adeno-associated virus 1 week after optic nerve crushing. Numbers of RGCs and of intrinsic photosensitive RGCs were determined through fluorescence microscopy. Image-forming activity of RGCs in mice was assessed using flash visual evoked potentials, the visual cliff test, and the visual water maze task. The non-image-forming activity of intrinsic photosensitive RGCs was assessed using the pupillary light reflex test. Results: CHET3 treatment increased the number of RGCs surviving after optic nerve injury, and it improved their electrophysiological response, visual acuity, contrast sensitivity, and the sensitivity of pupillary light reflex. These effects were associated with decreased RGC excitability. TASK-3 overexpression in sparse RGCs surviving long-term optic nerve injury restored their image- and non-image-forming activities. Conclusions: These results suggest that pharmacological activation or upregulation of TASK-3 may be a promising therapeutic strategy to promote vision recovery after optic nerve injury or in eye disorders associated with RGC degeneration.