Research ReportDegenerative alterations in the visual pathway after NMDA-induced retinal damage in mice
Introduction
Glaucoma is an optic neuropathy resulting from the death of retinal ganglion cells (RGC). In clinical studies, a loss of more than 50% of RGC has been reported to induce visual field loss. However, the initial loss of RGC does not lead to visual field loss in humans (Quigley et al., 1989). Possibly, a compensatory action of the visual cortex may protect the visual field against such a decrease. However, there is recent evidence that the RGC death that occurs in glaucoma leads to neuronal degeneration within the lateral geniculate nucleus (LGN), the major relay center between eye and visual cortex (Yücel et al., 2000). Further, it was reported that time- and region-dependent morphological changes had occurred in LGN at 120 days after intraocular pressure (IOP) was elevated in rats (Wang et al., 2000). These reports suggest that the visual field loss induced by glaucoma may not result only from RGC loss, but also from neuronal degeneration in LGN. However, no previous investigation has been made of time-dependent alterations along the retinogeniculate pathway (i.e., retina, optic tract, and LGN) after retinal injury in mice. In addition, the possible pathophysiological mechanisms underlying neuronal cell death in LGN following RGC loss remain uncertain.
Excessive activation of glutamate receptors by glutamate released from injured RGC is implicated in the glaucomatous RGC death process (Osborne et al., 1999). Glutamate is the principal excitatory neurotransmitter within the central nervous system (CNS), and it has been found to be increased in the vitreous body in glaucoma (Dreyer et al., 1996). In contrast, this fact was not confirmed by Honkanen et al. (2003). However, in fact the toxic effects of elevated levels of glutamate are predominantly mediated by the overstimulation of ionotropic receptors. Overstimulation of the class of these receptors that respond specifically to the glutamate analog N-methyl-d-aspartate (NMDA) leads to an overload of intracellular Ca2+. Such elevations in Ca2+ elicit various cytotoxic biochemical reactions including the activation of nitric oxide (NO) synthase and the generation of reactive NO free radicals. Two other classes of ionotropic receptors, which respond to the agonists kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropianate (AMPA), respectively, can also mediate Ca2+ overload when overstimulated, but they are somewhat less permeable to this ion than the NMDA receptor (NMDAR). In fact, a single intravitreal injection of NMDA has been reported to damage the cells in GCL and the IPL without affecting the other retinal layers in rats 7 days after the injection (Akaike et al., 1998). Among the glutamate receptors, the NMDA receptor's role in cell death has been extensively studied: excessive doses of NMDA induce apoptotic cell death of RGC and amacrine cells in rat retina (Lam et al., 1999, Inomata et al., 2003). Furthermore, it has been reported that NMDAR positive cells are either RGC or amacrine cells (Jakobs et al., 2007). In addition, a previous study has shown that NMDAR-mediated neurotoxicity in the RGC is dependent on the influx of extracellular Ca2+ (Sucher et al., 1997). In fact, blockade of glutamate activity by modulation of its receptors has been advocated as an important strategy for neuroprotection in glaucoma, and memantine, an NMDAR antagonist, displays a neuroprotective effect in experimental glaucoma (Li et al., 2002, Yücel et al., 2006). In either case, the animal model employed in the present study (involving intravitreal injection of NMDA) exhibits high sensitivity and stability, as well as good reproducibility, and is widely used for investigating the mechanisms underlying neuronal cell death in the retina (Yoneda et al., 2001). We therefore used it to investigate time-dependent alterations in the murine LGN following NMDA-induced retinal damage.
Section snippets
NMDA-induced retinal damage
Intravitreal injection of NMDA at 40 nmol/eye decreased both the cell-count in the GCL and the thickness of the IPL in the retina, as compared with those in the non-treated control retina (Fig. 1). The cell-count in GCL was decreased to 85.3, 47.6, 38.5, 32.5, 29.8, and 29.6% of control at 1, 3, 7, 30, 90, and 180 days, respectively, after NMDA injection. The thickness of IPL was increased to 138.8% of control at 1 day after the NMDA injection (Fig. 1B and I), then time-dependently decreased to
Discussion
In the present study, unilateral intravitreal injection of NMDA induced neuronal damage that was detected, in turn, in RGC, the optic tract, and in neurons contralateral dLGN, and contralateral vLGN-l, the maximal extent of the neuronal damage in these tissues (versus control, non-treated mice) being about 70, 60, 18, and 10%, respectively. This suggests that the retinal damage induced by intravitreal injection of NMDA in mice lead to neuronal degeneration in the LGN connected to that
Animals
Male adult C57BL/6J mice weighing 20–32 g (Clea Japan, Inc. Fujimiya, Japan) were kept under lighting conditions of 12 h light and 12 h dark. All experiments were performed in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and were approved and monitored by the Institutional Animal Care and Use Committee of Gifu Pharmaceutical University.
NMDA injection
Mice were anesthetized with 3.0% isoflurane (Merck, Osaka, Japan) and maintained with 1.5% isoflurane in 70% N2O
Acknowledgments
This study was supported in part by Grants-in-Aid for exploratory research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (Nos. 18209053 and 18210101).
References (60)
- et al.
Patterns of expression of brain-derived neurotrophic factor and tyrosine kinase B mRNAs and distribution and ultrastructural localization of their proteins in the visual pathway of the adult rat
Neurosci.
(2006) - et al.
Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family
Neuron
(1990) - et al.
Subicular dendritic arborization in Alzheimer's disease correlates with neurofibrillary tangle density
Am. J. Pathol.
(2003) - et al.
Neuronal density, size and shape in the human anterior cingulate cortex: a comparison of Nissl and NeuN staining
Brain Res. Bull.
(2004) - et al.
Changes of parvalbumin immunoreactive neurons and GFAP immunoreactive astrocytes in the rat lateral geniculate nucleus following monocular enucleation
Neurosci. Lett.
(2006) - et al.
Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase
J. Biol. Chem.
(1999) - et al.
Neuroprotective effects of interleukin-6 on NMDA-induced rat retinal damage
Biochem. Biophys. Res. Commun.
(2003) - et al.
Specific neuronal protein: a new tool for histological evaluation of excitotoxic lesions
Physiol. Behav.
(2002) - et al.
Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system
Neurosci.
(1992) - et al.
Astrocytes play a role in regulation of synaptic density
Brain Res.
(1987)
Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma
Am. J. Ophthalmol.
Role of NMDA receptor functional domains in excitatory cell death
Neuropharmacology
Expression of members of the trk family in the developing postnatal rat brain
Brain Res. Dev. Brain Res.
Neurotrophin signaling through the p75 neurotrophin receptor
Prog. Neurobiol.
Molecular basis of glutamate toxicity in retinal ganglion cells
Vision. Res.
Nitric oxide, microglial activities and neuronal cell death in the lateral geniculate nucleus of glaucomatous rats
Bain Res.
Brain-derived neurotrophic factor (BDNF) prevents lesion-induced axonal die-back in young rat optic nerve
Brain Res.
Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system
Neurosci.
Interleukin-1β mediates ischemic injury in the rat retina
Exp. Eye Res.
Axotomy-induced neuronal death and reactive astrogliosis in the lateral geniculate nucleus following a lesion of the visual cortex in the rat
J. Comp. Neurol.
Techniques for evaluating neuronal death of the retina in vitro and in vivo
Nippon Yakurigaku Zasshi
Nonneuronal cells mediate neurotrophic action of vasoactive intestinal peptide
J. Cell Biol.
The astrocytic response to afferent activity blockade in chick nucleus magnocellularis is independent of synaptic activation age and neuronal survival
J. Neurosci.
Origins of crossed and uncrossed retinal projections in pigmented and albino mice
J. Comp. Neurol.
Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma
Arch. Ophthalmol.
Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases
J. Neurosci.
Brain-derived neurotrophic factor-like immunoreactivity in the adult rat central nervous system predominantly distributed in neurons with substantial amounts of brain-derived neurotrophic factor messenger RNA or responsiveness to brain-derived neurotrophic factor
Neurosci.
Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex
Br. J. Ophthalmol.
Remote astrocytic response as demonstrated by glial fibrillary acidic protein immunohistochemistry in the visual cortex of dorsal lateral geniculate nucleus lesioned rats
Glia.
The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma
J. Clin. Invest.
Cited by (28)
Interaction of complement system and microglia activation in retina and optic nerve in a NMDA damage model
2018, Molecular and Cellular NeuroscienceCitation Excerpt :Therefore, a retina degeneration model was established, which is based on the intravitreal injection of N-methyl-d-aspartate (NMDA), a glutamate analogue. In this model, a fast degeneration of the inner retinal layers occurs (Ito et al., 2008; Nakano et al., 2011). Furthermore, NMDA is known to activate microglia in an inflammatory way, which then reinforces damage (Kaindl et al., 2012; Kuehn et al., 2017).
A freely available semi-automated method for quantifying retinal ganglion cells in entire retinal flatmounts
2016, Experimental Eye ResearchCitation Excerpt :To further validate the script and demonstrate its broad applicability for GON research, it was evaluated in three common mouse models of glaucomatous RGC degeneration. For the NMDA model, direct comparison to other studies is complicated due to differences in staining and counting methods, as well as NMDA concentrations and study end points within the various reports (De Groef et al., 2015; Ito et al., 2008; Kimura et al., 2015; Lebrun-Julien et al., 2009; Nakano et al., 2011; Nakazawa et al., 2007). Nevertheless, the dose-response correlation expected based on literature was clearly revealed by the script (Nakano et al., 2011).
Transplantation with retinal progenitor cells repairs visual function in rats with retinal ischemia-reperfusion injury
2014, Neuroscience LettersCitation Excerpt :Investigators observed that a decrease in the crosssectional area of neurons in the contralateral dLGN and SC was concomitantly associated with the RGC loss at 3 days post-operation [24]. Nuclear factor kappa-B is activated in the contralateral SC from 1 h to day 15 after retinal injury [4], and the expression of brain-derived neurotrophic factors (BDNF) and other neurotrophic factors in the LGN and SC are increased after retinal injury [6,20]. In the present study, we investigated the function and structural protective role of RPC transplantation into the SC in a rat model of RIR injury, and found that retinal progenitor cells survived in the SC for at least 8 weeks.
Neurovascular protective effect of FeTPPs in N-methyl-D-aspartate model: Similarities to diabetes
2010, American Journal of Pathology