Elevated Intracranial Pressure in Mice Causes Retinal Ganglion Cell Loss, Dysfunction, and Hypoxia

Abstract

Purpose : Elevated intracranial pressure (ICP) can result in multiple neurologic sequelae and inducible models of ICP elevation are lacking in model organisms. We modified a model for ICP elevation and tested the hypothesis that elevated ICP impacts retinal ganglion cells (RGCs).

Methods : A published technique from our lab (Nusbaum, et al., 2015) was modified to allow for use in C57BL6 mice. This technique allows for the modulation and measurement of ICP in living, awake mice using of an artificial CSF (ACSF) infusion apparatus and a wireless pressure monitoring system. 36 animals were used in the study, including experimental mice with elevated ICP (N = 17) and controls (N = 19). Anatomic (fundus photography, OCT), behavioral (contrast-dependent OKR), and electrophysiologic (whole field flash ERG) properties of the visual system were assessed in living animals at baseline and after 2 weeks. Post-mortem studies (RGC and retina histology, optic nerve TEM) were performed after 2 weeks.

Results : The mean ICP was 14.68 ± 1.64mmHg in the experimental group and 7.85 ± 1.07mmHg in the control group. Fundus photography revealed papilledema, loss of physiologic cupping, and engorgement of the optic nerve head. OCT confirmed these findings and showed a reduction in the thickness of the ganglion cell layer. ERG analysis showed diminished growth of the positive scotopic threshold response (pSTR) amplitude with increasing flash intensity. Measurement of the contrast-dependent OKR detected reduced photopic and scotopic contrast sensitivity. Retinal flat mounts stained for the RGC markers Tuj1 and RBPMS showed a reduction of 22-35% depending on antibody and retinal location. TEM of the optic nerve showed variable signs of injury and a global reduction in axon count of 33%. Retinal sections revealed increased expression of hypoxia-inducible factor (HIF)-1 alpha which was preferential to the ganglion cell layer.

Conclusions : Injury from elevated ICP appears to preferentially impact RGCs and their axons and may occur via a hypoxic mechanism. It is possible to model human diseases of elevated ICP such as idiopathic intracranial hypertension and spaceflight associated neuro-ocular syndrome in mice. Modeling of diseases of imbalance between ICP and intraocular pressure, such as glaucoma, is also possible.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.