August 16, 2012

Light Sensitivity Restored in Blind Mice

Retinal degeneration diseases such as retinitis pigmentosa affect approximately one of every 3,000 people worldwide. Although retinal chip prosthetics, gene therapy, and embryonic stem cell therapy have all been used to restore light sensitivity in either model organisms or humans, they are highly invasive and/or irreversible and may have undesirable, even dangerous, side effects. Researchers led by Dr. Richard Kramer of the Vision Science Graduate Group, Department of Molecular and Cell Biology, University of California, Berkeley, recently succeeded with an alternative, minimally invasive, and reversible strategy. Kramer and his team demonstrated that intravitreal injection of a small molecule K+ channel "photoswitch" called acrylamide-azobenzene-quaternary ammonium (AAQ) photosensitizes the retina (in vitro) of blind C3H/HeJ (000659) mice and restores light-driven behavior of these mice (in vivo) (Polosukhina et al. 2012). These findings indicate that AAQ could restore some light sensitivity in humans with end-stage retinal degeneration.

AAQ

AAQ allows researchers to control neuronal excitability – the speed of neuronal firing. Depending on the wavelengths that stimulate it, AAQ photoisomerizes to one of two forms. When exposed to long wavelengths (e.g., 500 nm), it isomerizes to the trans form, blocks K+ channels, and increases neuronal excitability; when exposed to short wavelengths (e.g., 380 nm), it isomerizes to the cis form, unblocks K+ channels, and decreases neuronal excitability.

The C3H/HeJ mouse

000659
The C3H/HeJ mouse is used in a wide variety of research areas, including cancer, immunology and inflammation, sensorineural, and cardiovascular biology. Along with other Jackson Laboratory C3H substrains, it is homozygous for the retinal degeneration 1 mutation (rd1) of the β-subunit of cGMP phosphodiesterase-6 gene (Pde6brd1), which causes blindness (nearly complete degeneration of rods and cones) by weaning age (three weeks old).

AAQ restores light sensitivity to blind C3H mice

Kramer and his colleagues analyzed AAQ's ability to restore light sensitivity to C3H retinas in vitro and in vivo. Their key findings are summarized below:

  • AAQ-treated C3H retinas exposed to 380 nm wavelengths are rapidly and significantly photosensitized, exhibiting an average three-fold increase (upto eight-fold) in the firing rate of retinal ganglion cells (RGCs – the cells that encode virtually all the visual information that reaches the brain)
  • Retinal amacrine and bipolar cells govern most AAQ-mediated RGC light responses
  • The brightness of light to which AAQ-treated retinas are sensitive to is similar to natural outdoor light
  • AAQ-mediated retinal responses have a high spatial resolution: AAQ’s ability to photosensitize RGCs in vivo can likely be considerably improved by refining intravitreal drug delivery techniques
  • AAQ restores a substantial – though not wild-type C57BL/6J (B6J, 000664) – pupillary light reflex to blind C3H mice
  • AAQ normalizes (to wild-type B6J level) the light avoidance behavior of blind C3H mice
  • AAQ mediates a light-induced decrease in exploratory behavior – as it does in wild-type B6J mice

In summary, Kramer and colleagues suggest that the AAQ photoswitch approach is either comparable to or better (relatively non-invasive, reversible, safer) than other methods for restoring some light sensitivity to people with late stage retinal degeneration .

Jackson Laboratory resources for eye research