Dopamine receptor loss of function is not protective of rd1 rod photoreceptors in vivo

[摘要] Purpose: The retinal degeneration (rd1)mouse undergoes a rapid loss of rod photoreceptors due to a defect inthe cGMP-phosphodiesterase gene. We have previously demonstratedthat dopamine (DA) antagonists or DA depletion blocks photoreceptordegeneration and that DA is necessary for photoreceptor degeneration inthe rd1 mouse retinal organ culture model. Antagonists foreither D1- or D2-family DA receptors are protective in rd1organ cultures. Methods: To determine whetherphotoreceptor survival can be increased in vivo in the rd1mouse, we used both a pharmacological and a genetic approach. Thepharmacological approach involved three techniques to administer6-hydroxydopamine (6-OHDA) in an attempt to deplete DA in postnatalmouse retina in vivo. As a genetic alternative, DA receptor signalingwas inactivated by crossbreeding rd1 mice to D1, D2, D4, and D5knockout mice to create four lines of double mutants. Results: Pharmacological DA depletionwas incomplete due to the limiting size of the postnatal mouse eye andthe lethality of systemic inhibition of DA signaling. In all four linesof double mutants, no increase in rod photoreceptor survival wasobserved. To determine whether protection of rd1 photoreceptorsby inhibition of dopaminergic signaling is a result of conditionsspecific to the organ culture environment, we grew in vitro retinasfrom the four lines of double mutant mice for four weeks. Again, noincrease in photoreceptor survival was seen. Finally, three triplemutants were generated that lacked two DA receptors (D1/D2; D1/D4; andD2/D4) on a rd1 background. In all three cases, rodphotoreceptors were not protected from degeneration. Conclusions: The dramatic protection of rd1rod photoreceptors by inhibition of DA signaling in organ culture hasnot been reproduced in vivo by either a pharmacological approach, dueto technical limitations, or by genetic manipulations. The possiblerole of compensatory effects during retinal development in DA receptordeficient mice is considered.

[学科分类] 生物化学/生物物理