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Guofu Shen, Derek Nusbaum, Benjamin J Frankfort; Optic nerve and retinal ganglion cell degeneration after two weeks of intracranial pressure (ICP) elevation in mice. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
To establish normal ranges and diurnal curves of ICP in freely moving C57Bl/6 mice. To confirm that ICP can be elevated experimentally for up to 2 weeks.
12-week old, male, C57Bl/6 mice were included in this study and maintained according to a standard 12 hour light-dark cycle. A radiofrequency transmitter for pressure monitoring and a custom cannula for the instillation of ACSF were placed in the subarachnoid space (Nusbaum et. al. 2015). Mice were allowed to range freely within a custom caging system. Normal ICP was continuously monitored for 1-2 week after surgery. ICP data were collected through wireless receivers for later offline analysis. For ICP elevation experiments, the infusion of ACSF was driven by gravity and the level of ICP adjusted manually. After maintaining ICP at approximately 20 mmHg for 2 weeks, the visual function of 4 mice was evaluated through OKR and whole field bilateral ERGs, and the results were compared with the data collected from control mice exposed to ICP surgery but without ICP elevation. Structural changes, such as RGC count and axon number within the optic nerve were also compared using immunofluorescence with Tuj1 staining and transmission electron microscopy, respectively.
Control mice showed a higher ICP level and more ICP variance at night, consistent with the nocturnal habitat of mice. Elevation of ICP to approximately 20 mmHg for two weeks caused a significant decrease of RGC number. In the central retina, the RGC density decreased from 4226±255 (n=20 regions from 3 normal ICP mice) to 2926±149 (n=44 regions from 6 elevated ICP mice). In the surrounding retina, similar changes were observed. Increased axonal degeneration (blebbing, distortion and rupture of myelin sheaths, vacuolization of axons) and significant axon loss was observed in the optic nerve nerves of mice exposed to elevated ICP. Analysis of OKR and ERG are still ongoing. The IOP of the animals was not changed by the ICP increase.
We successfully validated a novel experimental system for the monitoring and manipulation of ICP in active, awake mice for up to 2 weeks. With this animal model, a close correlation between the ICP elevation and function/structure deterioration was observed. This model can be used to study both the effects of ICP change and alteration of the ICP-IOP gradient in a variety of ophthalmologic and neurologic conditions.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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