Changes in the inner and outer retinal layers after acute increase of the intraocular pressure in adult albino Swiss mice
Introduction
Previous studies on ocular hypertensive mice models have focused predominantly on degenerative changes of the retinal ganglion cell (RGC) population and their axons in the retinal fibre layer and the optic nerve (Aihara et al., 2003a, Aihara et al., 2003b, Buckingham et al., 2008, Howell et al., 2007, Jakobs et al., 2005, Salinas-Navarro et al., 2009a, Salinas-Navarro et al., 2010, Schlamp et al., 2006, Soto et al., 2008). Following the changes at the RGC population, other retinal neuronal populations may also be affected (Bayer et al., 2001a, Bayer et al., 2001b, Mittag et al., 2000) including the inner (Panda and Jonas, 1992a) and outer nuclear layers of the retina (Nork et al., 2000, Panda and Jonas, 1992b). Affectation of other non-RGC neuronal populations in the retina has been shown in a number of morphological and functional studies that have used electroretinogram (ERG) recordings and the measurement of the thickness of the inner and outer retinal layers (Fazio et al., 1986, Korth et al., 1994, Salinas-Navarro et al., 2009a). Experimental models of elevated IOP (Bui et al., 2005, Chauhan et al., 2002, Feghali et al., 1991, Fortune et al., 2004, Holcombe et al., 2008, Kong et al., 2009) have shown important alterations of several ERG components, including the scotopic threshold response (STR), the a- and b- waves, which are associated with RGCs, photoreceptors and bipolar cells, respectively.
To further study the mechanisms by which elevated IOP causes retinal damage in adult albino mice we have used an ocular hypertension (OHT) induced retinal damage model, based on laser photocoagulation of the perilimbal and episcleral veins (Salinas-Navarro et al., 2009a, Salinas-Navarro et al., 2010). A recent study has shown in adult albino Swiss mice that lasering of the limbal tissues results in rapid elevation of the IOP which in turn results shortly after in diffuse as well as focal loss of RGCs, that adopted the form of pie-shaped wedges with their vertex located towards the optic nerve, and exhibited variable sizes ranging from a small sector to several quadrants of the retina (Salinas-Navarro et al., 2009a). Moreover, following elevated IOP there were permanent diminutions of the scotopic threshold response (STR) associated with the loss of the great majority of RGCs, indicating the value of noninvasive functional ERG losses associated with RGC loss in adult rodents (Alarcón-Martínez et al., 2009, Salinas-Navarro et al., 2009a). In addition there were also permanent diminutions of the major components of the ERG, the a- and b- waves, as well as lengthening of their implicit times, all of which imply severe alterations of the inner and outer nuclear layers of the retina (Salinas-Navarro et al., 2009a). In the present studies we have extended previous observations and have further studied short and long-term, qualitatively and quantitatively, functionally and morphologically, the retinal changes secondary to OHT in adult albino Swiss mice, not only at the outer retinal neurons but also at the neurotransmitter level. We present evidence indicating that following laser injury to the aqueous outflow pathways in the Swiss mice there is a functional impairment as well as retinal degeneration that affects the inner and outer synapse and nuclear layers, resulting in alterations of the inner and outer retinal circuitries. Short accounts of this work have been published in abstract form (Pinilla et al., 2008; IOVS ARVO-E-Abstract 5482).
Section snippets
Animals: handle and care
Experiments were performed on 15 adult albino Swiss male mice (40–45 g), obtained from the breeding colony of the University of Murcia (Murcia, Spain). Mice were housed in temperature and light controlled rooms with a 12 h light/dark cycle and had food and water ad libitum. Light intensity within the cages ranged from 9 to 24 luxes. Animal manipulations followed institutional guidelines, European Union regulations for the use of animals in research and the ARVO statement for the use of animals in
Laser-induced IOP values
There was some variability among the maximum IOP values registered from the lasered-eyes, within each of the animals and the subgroups processed at different survival intervals, but in general the results were rather consistent (Fig. 1A–C).
Overall our data show a similar time course elevation of the IOP for all groups of mice analyzed (Fig. 1A–C). There was an important increase of the IOP by 24 h after lasering, to twice its baseline value that remained elevated for the following four days and
Discussion
Various types of retinal injury have been proposed to study adult rodent RGCs in an effort to correlate their findings with the human glaucomatous optic neuropathy. These include optic nerve axotomy (Aguayo et al., 1987, Chidlow et al., 2005, Nadal-Nicolás et al., 2009, Parrilla-Reverter et al., 2009a, Parrilla-Reverter et al., 2009b, Whiteley et al., 1998), transient ischemia of the retina (Avilés-Trigueros et al., 2003; Lafuente et al., 2002, Lopez-Herrera et al., 2002, Mayor-Torroglosa
Acknowledgements
The authors would like to thank the technical contribution of Isabel Cánovas, José M. Bernal and Leticia Nieto. This work was supported by research grants from the Regional Government of Murcia, Spanish Ministry of Science and Innovation and Fundaluce; FIS PIO06/0780 (MPVP); 04446/GERM/07, SAF 2009-10385; RD07/0062/0001 (MVS), FIS PI04/2399 (IP), BFU2009-07793/BFI, RD07/0062/0012, Fundaluce, ONCE (NC), RD07/0062/0008 (PdlV).
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These authors contributed equally to this work.