Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice

Abstract

Elevated intracranial pressure (ICP) can result in multiple neurologic sequelae including vision loss. Inducible models of ICP elevation are lacking in model organisms, which limits our understanding of the mechanism by which increased ICP impacts the visual system. We adapted a mouse model for the sustained elevation of ICP and tested the hypothesis that elevated ICP impacts the optic nerve and retinal ganglion cells (RGCs). ICP was elevated and maintained for 2 weeks, and resulted in multiple anatomic changes that are consistent with human disease including papilledema, loss of physiologic cupping, and engorgement of the optic nerve head. Elevated ICP caused a loss of RGC somas in the retina and RGC axons within the optic nerve, as well as a reduction in both RGC electrical function and contrast sensitivity. Elevated ICP also caused increased hypoxia-inducible factor (HIF)-1 alpha expression in the ganglion cell layer. These experiments confirm that sustained ICP elevation can be achieved in mice and causes phenotypes that preferentially impact RGCs and are similar to those seen in human disease. With this model, it is possible to model human diseases of elevated ICP such as Idiopathic Intracranial Hypertension and Spaceflight Associated Neuro-ocular Syndrome.

Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update

“…Sustained ICP elevation is correlated with increased levels of HIF-1α in the retinal ganglion cell layer, and some models have demonstrated presumed breakdown of the blood retinal and blood optic nerve barrier with vascular leakage into the interstitial space of the ONH and subretinal space in the peripapillary region. 19 In addition, increased ICP that resolves upon return to the terrestrial 1 G environment might produce other local structural changes that might induce secondary inflammation or oxidative stress and the residual optic nerve sheath distension and choroidal folds after return might suggest that the elasticity of the optic nerve sheath trabecular fibers or collagen structures might be permenantly altered by spaceflight independent of ICP. Further studies are needed to determine the role if any of local vascular stasis, inflammation, or oxidative stress to the pathophysiology of SANS in relation to ICP.…”

Intracranial pressure modulates aqueous humour dynamics of the eye

“…; Shen et al . ). The discovery of a central regulator of aqueous humour dynamics in rats may offer a new target for glaucoma treatment.…”

“…Efferent modulation of C and IOP was revealed here via acute steps in ICP. Feedback response time was not investigated nor whether the mechanism adapts or fatigues to sustained activation, given that chronic ICP elevation was found to cause optic nerve degeneration in mice (Nusbaum et al 2015;Shen et al 2018). The discovery of a central regulator of aqueous humour dynamics in rats may offer a new target for glaucoma treatment.…”

“…; Shen et al . ). According to the CSFP hypothesis (Berdahl & Allingham, ) the mechanical insult to RGC axons depends not just on IOP but on the translaminar pressure (TLP) across the lamina cribosa, which is determined by the difference between IOP and CSFP.…”

“…CSF fills the ventricles of the brain and surrounds the CNS to form a continuous fluid-filled compartment. The fluid applies pressure on the optic nerve head that can cause papilloedema and nerve degeneration if too high (Hedges, 1975;Nusbaum et al 2015;Shen et al 2018). According to the CSFP hypothesis (Berdahl & Allingham, 2010) the mechanical insult to RGC axons depends not just on IOP but on the translaminar pressure (TLP) across the lamina cribosa, which is determined by the difference between IOP and CSFP.…”