304

best characterized mammalian genomes. Mice are inexpensive to breed and are amenable to an array of genetic manipulations (see Peters et al., 2007). These properties allow the role of individual genes or molecular pathways to be assessed within a controlled genetic environment (John et al., 1999; Smithies and Maeda, 1995).

Mice are suitable models for studying IOP elevation in glaucoma

Detailed molecular understanding of aqueous humor (AqH) drainage and its abnormalities in glaucoma is an important goal for glaucoma research. This understanding will guide the development of new strategies to protect neurons from pressure-induced insults. Pressure-induced insults are key factors in the degeneration of RGCs in glaucoma. The AqH drainage structures play an important role in determining IOP and its elevation in glaucoma. The mouse is well suited for studying AqH drainage because it has similar AqH drainage structures to humans (Smith et al., 2001). The two types of outflow pathways present in humans, conventional and uveoscleral, exist in mice (see John et al., 1999; Lindsey and Weinreb, 2002). Both species have an endothelial-lined Schlemm’s canal (SC) and a trabecular meshwork (TM) consisting of layers of well-organized trabecular beams covered with endothelial-like trabecular cells. These drainage structures reside in the angle of the eye (Smith et al., 2001; Gould et al., 2004b). The organizational similarity extends to drainage structure development and the genes that influence it (Gould et al., 2004b). The documented similarities between mice and humans in drainage structure anatomy, in functional responses to drugs that inhibit aqueous production and facilitate outflow and in values for various outflow parameters (Aihara et al., 2003; Avila et al., 2003), indicate that mice represent very suitable models for studying IOP and its glaucomaassociated elevation (John, 2005).

Tools for glaucoma research

The small size of the mouse eye initially hampered the use of the mouse as a glaucoma model. Various techniques of ocular analysis have been adapted for

mice, including slit-lamp gonioscopy, indirect ophthalmoscopy, and IOP measurement (Smith et al., 2002). Because of its importance for all studies of glaucoma, we next discuss IOP assessment.

Accurate IOP measurements are fundamental to the study of glaucoma

In mice, the most accurate and precise measurements are achieved using invasive cannulation methods. In the microneedle system, a very fine fluid-filled glass microneedle is inserted into the anterior chamber. The needle is connected to a pressure transducer and the pressure reading is monitored on a computer (Savinova et al., 2001; John and Savinova, 2002). A second system available is an adaptation of the servo-null micropipette system (SNMS) that was developed for measuring pressure in structures smaller than 25 mm (Avila et al., 2001). Although cannulation methods have the disadvantage of penetrating the eye, limiting the number of reasonable longitudinal readings, large numbers of genetically identical mice of different ages can be evaluated. This provides an accurate record of IOP for any given population/strain.

Various tonometric devices have been adapted for use in mice based on devices for assessing IOP in humans (for recent review, see Pang and Clark, 2007). Only the optical interferometry tonometer (OIT) and impact/rebound (I/R) tonometer have been directly compared to the more accurate invasive method in the same eye in vivo (Filippopoulos et al., 2006; Morris et al., 2006) and so these are the best validated instruments. We, and others, cannot obtain accurate or reliable readings using the Tono-Pen tonometer (John et al., 1997; Reitsamer et al., 2004; Dalke et al., 2005; Pease et al., 2006).

It is clear that with appropriate care accurate noninvasive measurements are achievable in some mouse strains. However, inappropriate use in strains with corneal abnormalities or in strains for which accurate in vivo validation has not been performed can be very misleading (differing corneal properties between strains with outwardly normal corneas affect accuracy). For some of these strains that have relatively normal corneas, correction factors can be determined (Nissirios et al., 2007). The commonly used mouse model of glaucoma