Muneeb, you have raised an excellent question. We may not have an answer as to why mouse don’t have lamina cribrosa, but your remark that mouse would be non-ideal model for glaucoma is well taken.

In humans, the lamina cribrosa has been implicated as the site of injury in glaucoma , then, why are we using mice for glaucoma research if these creatures don’t have LC? Perhaps, the researchers who are using mice as glaucoma model can answer your valid question.

I don’t believe LC can ever be the primary site of injury in glaucoma in view of orderly loss of NFs in glaucoma. For the orderly loss to occur the NFs have to be lying loose as they in the prelaminar area, and not when they are fixed in the pores of LC and thus couldn't be separated. Therefore, prelaminar area appears to be the more likely site of injury in glaucoma.

If the mice without LC are developing glaucoma then it means that glaucoma can develop without the involvement of LC.

Thank you for your answer. I think there are two important points that appear relevant to me.

1. Is glaucoma possible (i mean natural/ideal glaucoma and not the experimentally induced one) in murine models? If no, then LC may well be quire relevant and may hold the answer to this intriguing puzzle. If yes, then LC may be a disguise, a bystander, irrelevant, or just partially relevant.

2. Is human glaucoma different from the murine glaucoma? That will be quite a great idea to pursue and will save us lot of money that we will otherwise be wasting on experiments conducted on murine models.

I would love to have your detailed perspective on this.

Following is my response to your very inquisitive questions.

Is glaucoma possible (i mean natural/ideal glaucoma and not the experimentally induced one) in murine models?

In my opinion we may produce acute glaucoma in animals including rodents very easily but to produce chronic glaucoma is a very different story. Chronic glaucoma is indeed a chronic disease as it takes time to develop. In humans chronic glaucoma is caused by IOP varying from normal range to moderately elevated range. But, when the IOP becomes extremely elevated then it becomes acute glaucoma which is not the topic of our research. The pathophysiology of the acute glaucoma is totally different than that of the chronic glaucoma. In acute glaucoma the extremely high IOP will compress the circulation of the retina and would cause immediate necrosis of retina and blindness.

Whereas, chronic glaucoma is caused by moderately elevated IOP ( less than the acute glaucoma range IOP). Therefore, in experimental chronic glaucoma we will have to elevate the IOP only moderately and not high enough to the range of acute glaucoma levels otherwise immediate death of the retina will occur and it will spoil all the research associated with chronic glaucoma.

There are other things associated with human’s chronic glaucoma such as preperimetric and perimetric glaucoma. Then perimetric glaucoma has continuous stages until the endstage. It is hard to diagnose glaucoma based on cupping paradigm in humans so I don’t know how the researchers are diagnosing experimental chronic glaucoma in animals.

My straight answer to your question: the experimental chronic glaucoma can never be ideal and I believe this is the reason we see different results from different research centers in animal studies.

Is human glaucoma different from the murine glaucoma?

I don’t have answer to your question since I have not studied animal glaucomas. But I have read cupping of glaucomatous discs in dogs which shows that vets are also following human’s cupping paradigm.

My personal belief: we don’t need any animal experimental glaucoma models. We have abundance of chronic glaucoma humans in every stage of glaucoma and with every range of IOP from NTG to HTG. Moreover, in glaucoma we can directly see the morphological changes occurring in chronic glaucoma discs from the early stages to end stage in the same patient with fundus camera.

We have OCT which is said to be as good as histology, then why do we need experimental animals when we have humans with real glaucoma? I have no answer.

I am perplexed - the mouse does have a lamina cribrosa although it is very fine with the tiny optic nerve axons passing through holes in the sclera - this paper (John, S. W., Smith, R. S., Savinova, O. V., Hawes, N. L., Chang, B., Turnbull, D., ... & Heckenlively, J. R. (1998). Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Investigative ophthalmology & visual science, 39(6), 951-962.) shows the murine lamina cribrosa in figure 3G and how it is lost in the cupped disc in a glaucomatous mouse in figure 3H & I. Now I grant you that May, C. A., & Mittag, T. (2006). Optic nerve degeneration in the DBA/2NNia mouse: is the lamina cribrosa important in the development of glaucomatous optic neuropathy?. Acta neuropathologica, 111(2), 158-167 says that the species don't have a lamina cribrosa, but I think the problem is that it is very fine and not easily recognised with elastin fibres not collagen. Quigley's paper (Quigley, H. A., & Cone, F. E. (2013). Development of diagnostic and treatment strategies for glaucoma through understanding and modification of scleral and lamina cribrosa connective tissue. Cell and tissue research, 353(2), 231-244.) shows that the muose is stil a valuable model for glaucoma.

Thank you David for your answer. The papers you cited seem to be giving rise to a controversy in basic ophthalmology. It boils down to a very simple question. Are our imaging, dissection and microscopy techniques so weak that one group of investigators see a lamina cribrosa and the other group does not. Your definition of a lamina cribrosa is simple and strong (sclera behind the optic nerve head through which axons of the optic nerve pass). Identifying this structure with microscopy is not a herculean task. If, it is not being seen/sighted, the indication would be the absence of lamina cribrosa. Not only that, why does an animal of such a small size and anatomy need a lamina cribrosa? is an important question which no investigator seems to be interested in. What is the function of lamina cribrosa per se? will tell us Why it should be present/absent in a particular organism.

You provided evidence from literature which suggests that mice do have a lamina cribrosa (probably thinking that lamina cribrosa is a mammalian trait and hence should be present in mice also- confirmation bias). Here are a few papers that say mice do NOT have a lamina cribrosa. This makes my question very profound and meaningful. And perhaps subtle also.

https://www.ncbi.nlm.nih.gov/pubmed/16453144

http://iovs.arvojournals.org/article.aspx?articleid=2163273

Article Comparative study of the lamina cribrosa and the pial septa ...

Article The Morphology and Spatial Arrangement of Astrocytes in the ...

Regarding mice as a valuable model fro glaucoma, I think we can have small discussion or friendly debate on it. May be we write an anecdote for some journal together.

If there is no lamina cribrosa then the nerves would all leave the globe in a mass with no individual perforations through the sclera for each retinal ganglion cell axon. But papers such as Soto's (http://www.jneurosci.org/content/jneuro/28/2/548.full.pdf) show that mouse models of glaucoma can be used as valuable experimental models for human glaucoma.

I think there are three possible ways the sclera ends up at the optic nerve head:

1. It continues and completes the scleral ball we generally call eye ball. In this case, the nerve fibers have to perforate it at the ONH site leading to the cribriform appearance of the lamina (which actually is continuity of sclera). This perforated lamina or cribriform lamina would be refered to as Lamina cribrosa.

2. The sclera ceases its continuity and there is a hole in sclera at this site. The nerve fibers in this case can still move out of the globe but in a bundle which may or may not be arranged systematically. This makes such a model non-suitable for glaucoma.

3. The sclera continues in a different manner around the optic nerve and ensheaths it. Such an arrangement may be interesting but this model would again not be suitable for glaucoma research.