Abstract
Purpose :
It has been proposed that cerebrospinal fluid (CSF) can enter and leave the retina and optic nerve along perivascular spaces surrounding the central retinal vessels as part of an aquaporin-4 (AQP4) dependent ocular ‘glymphatic’ system. Here we have investigated if tracers injected in the CSF can enter the retina and optic nerve and if tracer uptake is susceptible to AQP4 deletion or changes in intraocular pressure (IOP).
Methods :
We injected fixable fluorescent dextrans and antibodies into the cisterna magna of wild-type and AQP4 deficient mice and measured their distribution in the optic nerve and retina by confocal microscopy. IOP was acutely changed by anterior chamber cannulation during cisternal tracer injections, in order to determine if changes in IOP altered CSF transport into ocular tissues.
Results :
We found that uptake of dextrans in the perivascular spaces and parenchyma of the optic nerve is highly sensitive to the cisternal injection rate, where high injection rates, in which dextran disperses fully in the sub-arachnoid space, led to uptake along the full length of the optic nerve. Accumulation of dextrans in the optic nerve did not differ significantly in wild-type and AQP4 knockout mice, and AQP4 was not expressed in the optic nerve head od wild-type mice. Dextrans did not enter the retina, even when IOP was reduced. Elevation of IOP reduced accumulation of fluorescent dextrans in the optic nerve head, and intravitreally injected dextrans left the retina via perivascular spaces surrounding the central retinal vessels. Non-specific antibodies accumulated in the perivascular and parenchymal areas of the optic nerve to a similar extent as dextran following cisternal injection. However, uptake of a cisternally injected AQP4-IgG antibody, derived from a seropositive neuromyelitis optica spectrum disorder (NMOSD) patient, was limited by AQP4 binding.
Conclusions :
We conclude that large molecules injected in the CSF can accumulate along the length of the optic nerve if they are fully dispersed in the optic nerve sub-arachnoid space but that they do not enter the retina. Intravitreally injected solutes can leave the eye along perivascular spaces surrounding the central retinal vessels.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.