Dopamine receptor loss of function is not protective of rd1 rod photoreceptors in vivo.
OBJECTIVE
The retinal degeneration (rd1) mouse undergoes a rapid loss of rod photoreceptors due to a defect in the cGMP-phosphodiesterase gene. We have previously demonstrated that dopamine (DA) antagonists or DA depletion blocks photoreceptor degeneration and that DA is necessary for photoreceptor degeneration in the rd1 mouse retinal organ culture model. Antagonists for either D1- or D2-family DA receptors are protective in rd1 organ cultures.


METHODS
To determine whether photoreceptor survival can be increased in vivo in the rd1 mouse, we used both a pharmacological and a genetic approach. The pharmacological approach involved three techniques to administer 6-hydroxydopamine (6-OHDA) in an attempt to deplete DA in postnatal mouse retina in vivo. As a genetic alternative, DA receptor signaling was inactivated by crossbreeding rd1 mice to D1, D2, D4, and D5 knockout mice to create four lines of double mutants.


RESULTS
Pharmacological DA depletion was incomplete due to the limiting size of the postnatal mouse eye and the lethality of systemic inhibition of DA signaling. In all four lines of double mutants, no increase in rod photoreceptor survival was observed. To determine whether protection of rd1 photoreceptors by inhibition of dopaminergic signaling is a result of conditions specific to the organ culture environment, we grew in vitro retinas from the four lines of double mutant mice for four weeks. Again, no increase in photoreceptor survival was seen. Finally, three triple mutants were generated that lacked two DA receptors (D1/D2; D1/D4; and D2/D4) on a rd1 background. In all three cases, rod photoreceptors were not protected from degeneration.


CONCLUSIONS
The dramatic protection of rd1 rod photoreceptors by inhibition of DA signaling in organ culture has not been reproduced in vivo by either a pharmacological approach, due to technical limitations, or by genetic manipulations. The possible role of compensatory effects during retinal development in DA receptor deficient mice is considered.
Ogilvie
Judith Mosinger
JM
Department of Biology, Saint Louis University, St Louis, MO 63103, USA. ogilviej@slu.edu
Hakenewerth
Angela M
AM
Gardner
Rachel R
RR
Martak
Joshua G
JG
Maggio
Virginia M
VM
D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival; D051379:Mice; D009924:Organ Culture Techniques; D011954:Receptors, Dopamine / Q000172:deficiency* / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology*
D011954:Receptors, Dopamine