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B.A. Berkowitz, R. Roberts, D. Goebel, H. Luan; Non–Invasive and Simultaneous Imaging of Retinal Layer–Specific Ion Demand . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5388.
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© ARVO (1962-2015); The Authors (2016-present)
Current methods do not analytically and specifically measure changes in retinal cellular calcium ion demand in vivo. Because Mn2+ ion is both a Ca2+ ion surrogate and a strong MRI contrast agent, we tested the hypothesis that high resolution (23.4 µm intraretinal resolution) manganese–enhanced MRI (MEMRI) can be used to non–invasively measure cellular demand for calcium simultaneously in distinct layers of the rat retina.
Mn+2 toxicity was assessed one month after systemic administration of MnCl2 to awake dark adapted control rats using the following metrics: retinal layer thickness (measured in vivo with MRI and ex vivo using thin slice histology), intraocular pressure (Tonopen XL), blood retinal barrier integrity (measured with dynamic contrast MRI), and retinovascular oxygenation ability (measured with functional MRI and a carbogen challenge). In separate controls rats, accumulation of Mn2+ ion in inner and outer retina during either light, dark, or flicker (4 Hz) adaptation was analytically assessed using MEMRI. MEMRI studies of dark adapted 8 mo and 11 mo control rats with photoreceptor degeneration are also presented.
Comparing the data for historic control rats and Mn+2 injected rats revealed no evidence (P > 0.05) for systemic (i.e., no animal deaths) or local (i.e., ocular and retinal) Mn+2 toxicity. Excellent agreement was found between the Mn+2–induced enhancement patterns in light and dark adapted retinas with known changes in retinal physiological activity in the inner and outer retina. Flicker stimulation following dark adaptation altered the outer retinal MEMRI signal (P < 0.05) but not that of the inner retina (P > 0.05). Older rats lacking photoreceptors had significantly (P < 0.05) supernormal MEMRI signal from inner retina.
MEMRI studies after systemic administration of non–toxic MnCl2 concentrations in control awake rodents allows robust detection of Mn2+ ion accumulation in inner and outer retina during visual stimulation. The Mn2+ ion accumulation accurately and precisely reflects previously established activity–dependent changes in the metabolic–calcium axis in specific retinal layers. Comprehensive MEMRI measures of retinal cellular calcium demand can now be initiated in a range of animal models to study normal development and aging, as well as to characterize genetically modified and pathologic rodent retinopathy models.
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