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J. M. Ogilvie, A. M. Hackenewerth, R. R. Gardner; Dopamine Receptor Loss of Function Is Not Protective of rd1 Rod Photoreceptors in vivo. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4400.
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© ARVO (1962-2015); The Authors (2016-present)
The rd1 mouse retina is among the best studied models of retinitis pigmentosa. The rod photoreceptors of the rd1 mouse degenerate in vivo or in organ culture by one month of age as a result of a defect in the β-subunit of the cGMP-phosphodiesterase gene. The molecular cascade that induces apoptosis in rd1 photoreceptors remains poorly understood. Dopamine is a neuromodulator affecting most, if not all, cell types in the vertebrate retina. We have discovered that dopamine antagonists from either the D1- or D2-receptor families completely block the degeneration of photoreceptors in the rd1 retinal organ culture model (Neurobiol Disease 2002, 10:33-40). Here we use a genetic approach to determine whether dopamine receptors play a role in rd1 photoreceptor survival in vivo.
rd1 mice were crossbred with animals deficient in D1, D2, D4, or D5 dopamine receptors to create four lines of double mutants, each one lacking one pathway of dopamine signaling. At postnatal day 21, eyecups were harvested, fixed in mixed aldehydes and embedded in Epon-Araldite. Photoreceptor survival in double mutant retinas was compared to that seen in each of the single mutant or wild type retinas.
Loss of function of any of the four dopamine receptors expressed in the vertebrate retina does not protect rd1 rod photoreceptors from degeneration, in spite of the observation that dopamine antagonists are protective in rd1 retinal organ cultures. Experiments currently underway will determine whether dopamine receptor loss of function will be protective of rd1 rod photoreceptors in retinal organ culture.
We have shown that the protective effects of dopamine receptor antagonists in retinal organ culture cannot be duplicated by deletion of each of the dopamine receptor subtypes in vivo. Several differences may explain these results. For example, the in vitro organ cultures may contain survival factors not present in vivo. Alternatively, the presence of multiple dopamine receptor subtypes or the possibility of heterodimerization may provide redundancy that is overcome by pharmacological, but not genetic, inhibition of function.
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