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M. O. Karl, S. Hayes, B. Nelson, K. Tan, B. Buckingham, T. A. Reh; Amacrine but Not Bipolar Cells Regenerate in the Adult Murine Retina After NMDA Neurotoxic Damage. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3062.
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Muller glia can serve as a source of new neurons after retinal damage in both fish and birds. Regeneration is complete in fish; in chicken limited to inner retinal neurons. Whether a similar process might occur in mammals is not conclusive.
To address this question in vivo we damaged adult mouse retina by intraocular injection of NMDA and two days later subsequently injected various growths factors up to 4 days. We also tested for bipolar cell differentiation by combining the last growth factor injection with Notch signaling inhibitor DAPT. To label proliferating cells BrdU was delivered intraocularly and -peritoneally.
NMDA neurotoxic damage leads to a loss of horizontal, amacrine and retinal ganglion cells. In NMDA treated retinas, several growths factors stimulated Muller glia proliferation, but the combination of FGF1 and insulin was most successful. NMDA damage, followed by FGF1/insulin injections in a line of mice in which green fluorescent protein (GFP) is expressed from the GAD67-promoter revealed that some of the progeny of Müller glia (BrdU+) differentiate into GAD67-expressing neurons (amacrine, ganglion, or horizontal cells). Some of the BrdU+ cells also expressed other markers of amacrine cells, including NeuN, calretinin and Prox1. However, we did not find any evidence of BrdU+ cells labeled with bipolar markers: chx10 or mGluR6-GFP. These results show that at least some type of retinal neurons can be regenerated from Muller glia following NMDA damage, but the types of neurons regenerated may be confined to those types that were lost.
Although Muller glia can be induced to proliferate, dedifferentiate and regenerate retinal neurons, most likely amacrine cells, in the adult mouse retina, this process is more limited than in chicken or fish retina.
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