a-model-of-glaucoma-induced-by-circumlimbal-suture-in-rats-and-mice

A Model of Glaucoma Induced by Circumlimbal Suture in Rats and Mice

The circumlimbal suture is a technique for inducing experimental glaucoma in rodents by chronically elevating intraocular pressure (IOP), a well-known ...

University of Melbourne

An increasing number of studies indicate that the optic nerve head of the eye is sensitive not only to changes in intraocular pressure (IOP), but also to intracranial pressure (ICP). This study examines changes to optic nerve and retinal structure in a rat model in response to a range of IOP and ICP levels using optical coherence tomography. Furthermore, we examine the functional sequelae of these structural changes by quantifying the effect of pressure changes on the electroretinogram. IOP elevation (10-90 mmHg) induces progressive deformation of the optic nerve head and retinal surface (P < 0.05), compression of the retina (P < 0.05) and bipolar cell (b-wave), and retinal ganglion cell (scotopic threshold response) dysfunction (P < 0.05). Simultaneously altering ICP (-5 to 30 mmHg) modifies these IOP-induced responses, with lower ICP (-5 mmHg) exacerbating and higher ICP (15-30 mmHg) ameliorating structural and functional deficits. Thus, the balance between IOP and ICP (optic nerve pressure gradient, ONPG = IOP - ICP) plays an important role in optic nerve integrity. Structural and functional parameters exhibit a two-phase relationship to ONPG, with structural changes being more sensitive to ONPG modification (threshold = -0.6 to 11.3 mmHg) compared with functional changes (threshold = 49.7-54.6 mmHg). These findings have implications for diseases including glaucoma, intracranial hypertension, and long-term exposure to microgravity.

The effect of intraocular and intracranial pressure on retinal structure and function in rats.

To consider whether a circumlimbal suture can be used to chronically elevate intraocular pressure (IOP) in mice and to assess its effect on retinal structure, function and gene expression of stretch sensitive channels. Anesthetized adult C57BL6/J mice had a circumlimbal suture (10/0) applied around the equator of one eye. In treated eyes ( = 23) the suture was left in place for 12 weeks whilst in sham control eyes the suture was removed at day two ( = 17). Contralateral eyes served as untreated controls. IOP was measured after surgery and once a week thereafter. After 12 weeks, electroretinography (ERG) was performed to assess photoreceptor, bipolar cell and retinal ganglion cell (RGC) function. Retinal structure was evaluated using optical coherence tomography. Retinae were processed for counts of ganglion cell density or for quantitative RT-PCR to quantify purinergic () or stretch sensitive channel () gene expression. Immediately after suture application, IOP spiked to 33 ± 3 mmHg. After 1 day, IOP had recovered to 27 ± 3 mmHg. Between weeks 2 and 12, IOP remained elevated above baseline (control 14 ± 1 mmHg, ocular hypertensive 19 ± 1 mmHg). Suture removal at day 2 (Sham) restored IOP to baseline levels, where it remained through to week 12. ERG analysis showed that 12 weeks of IOP elevation reduced photoreceptor (-15 ± 4%), bipolar cell (-15 ± 4%) and ganglion cell responses (-19 ± 6%) compared to sham controls and respective contralateral eyes (untreated). The retinal nerve fiber layer was thinned in the presence of normal total retinal thickness. Ganglion cell density was reduced across all quadrants (superior -12 ± 5%; temporal, -7% ± 2%; inferior -9 ± 4%; nasal -8 ± 5%). Quantitative RT-PCR revealed a significant increase in  gene expression (+11 ± 4%), whilst other genes were not significantly altered (). Our results show that circumlimbal ligation produces mild chronic ocular hypertension and retinal dysfunction in mice. Consistent with a sustained change to purinergic signaling we found an up-regulation of Entpd1.

Characterization of the Circumlimbal Suture Model of Chronic IOP Elevation in Mice and Assessment of Changes in Gene Expression of Stretch Sensitive Channels.

Age-related changes to the balance between the pressure inside the eye (intraocular pressure, IOP) and the pressure inside the brain (intracranial pressure, ICP) can modify the risk of glaucoma. In this study, we consider whether the optic nerve in older rat eyes is more susceptible to acute IOP and ICP modification. We systematically manipulate both ICP and IOP and quantify their effects on ganglion cell function (electroretinography, ERG), optic nerve structure (optical coherence tomography, OCT) and retinal blood flow (Doppler OCT). We show that ganglion cell function in older eyes was more susceptible to a higher optic nerve pressure difference (ONPD = IOP - ICP). This age-related susceptibility could not be explained by poorer blood flow with elevated ONPD. Rather, as ONPD increased the retinal nerve fibre layer showed greater compression, and the retinal surface showed less deformation in older eyes. Our data suggest that age-related changes to connective tissues in and around the rat optic nerve make it less flexible, which may result in greater strain on ganglion cell axons. This may account for greater functional susceptibility to higher optic nerve pressure differences in older rat eyes. Further studies in a species with a well-developed lamina cribrosa are needed to determine the clinical importance of these observations.

Article	Year
The effect of intraocular and intracranial pressure on retinal structure and function in rats. Physiological reports\| PubMed ID: 26290528	2015
Characterization of the Circumlimbal Suture Model of Chronic IOP Elevation in Mice and Assessment of Changes in Gene Expression of Stretch Sensitive Channels. Frontiers in neuroscience\| PubMed ID: 28239332	2017
Age-related changes in the response of retinal structure, function and blood flow to pressure modification in rats. Scientific reports\| PubMed ID: 29440700	2018

Da Zhao

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