Dendritic and synaptic plasticity of neurons in the human age-related macular degeneration retina

PURPOSE. To determine whether structural plasticity is evident in human retinal tissues in response to age-related macular degeneration (AMD). Remodeling events such as sprouting of neuronal processes and the reconnection of synapses are essential elements in repairing any damage to adult nervous tissues such as might occur in response to insults such as strokes or in AMD

Evoked expression of the glutamate transporter GLT-1c in retinal ganglion cells in human glaucoma and in a rat model

PURPOSE: Glaucoma is a common disease of the eye, a key characteristic consequence of which is the death of retinal ganglion cells. The cause of this loss is unknown, though glutamate-mediated toxicity has been implicated. Glutamate transporters are key regulators of glutamate; therefore, the purpose of the study was to determine whether unusual excitation is associated with unusual expression of one or more transporters. METHODS: The expression of a splice variant of the glutamate transporter GLT-1 (EAAT2) was examined in normal and glaucomatous retinas from humans and rats. RESULTS: In normal eyes of humans and rats, GLT-1c was expressed only in photoreceptors. In glaucoma, there was additional robust expression of GLT-1c in retinal ganglion cells, including occasional displaced ganglion cells. Conversely, cells such as displaced amacrine cells and amacrine cells were unlabeled. CONCLUSIONS: The induction of GLT-1c expression by retinal ganglion cells supports the notion that an anomaly or anomalies in glutamate homeostasis may be evident in glaucoma and that such anomalies selectively influence retinal ganglion cells. By analogy to in vitro experiments in which elevated glutamate levels induce expression of glutamate transporters, the authors hypothesize that expression of GLT-1c may represent an attempt by retinal ganglion cells to protect themselves against elevated levels of glutamate. Such anomalies in glutamate levels cannot be restricted to the ganglion cell layer, as this would not have affected displaced ganglion cells. GLT-1c may be a useful indicator of the extent of stress of the retinal ganglion cells and thus a tool for examining outcomes of potential therapeutic and experimental interventions

Characterization of retinal injury using ERG measures obtained with both conventional and multifocal methods in chronic ocular hypertensive primates. Invest Ophthalmol Vis Sci.

PURPOSE. To characterize, using both conventional and multifocal electroretinogram (ERG) recordings as well as histologic measures, retinal injury in the chronic ocular hypertensive primate model for experimental glaucoma. METHODS. Ocular hypertension was induced in the right eye of 7 cynomolgous monkeys, Macaca fascicularis, using laser injury to the aqueous outflow tissue at the anterior chamber angle. At 16 months after IOP elevation, ERG recordings were made from both eyes of all animals using both conventional and multifocal methods. After electrophysiological recording, animals were killed and retinal samples were radially sectioned for histologic analysis. RESULTS. Histologic measures showed that ocular hypertensive injury was largely or completely limited to a loss of retinal ganglion cells (RGCs). The degree of RGC loss was similar in central and peripheral retina. Amplitudes of conventional ERG responses were mostly unaffected in eyes having severe loss of RGCs, a finding that is consistent with limited injury to photoreceptors, bipolar cells, and amacrine cells. Peaks in both the first-and second-order multifocal ERG responses were attenuated in ocular hypertensive eyes, and amplitude of these peaks was highly correlated with the density of surviving RGCs. CONCLUSIONS. The results are consistent with a conclusion that both first-and second-order components of the multifocal ERG response from the monkey reflect a significant contribution from activity in RGCs and may provide a useful measure for the clinical diagnosis and management of glaucoma. (Invest Ophthalmol Vis Sci. 2001;42:127-136) T he chronic ocular hypertensive (COHT) primate, originally described by Gaasterland and Kupfer, 1 has been studied in a number of different laboratories as a model for glaucomatous injury to the retina and optic nerve. In this model, chronic elevation of intraocular pressure (IOP) results in retinopathy and neuropathy that reflect an apparently selective loss of retinal ganglion cells (RGCs) and their axons. 18 These findings support the notion that mfERG recordings may have utility in the diagnosis and management of glaucomatous injury to RGCs. We report here our results from histologic measures of retinal injury as well as measures of ERG responses obtained using both conventional and multifocal techniques in the COHT primate. Some preliminary findings from this study have been published previously in a brief report. 19 METHODS Animal Subjects Seven young adult female cynomolgous monkeys, Macaca fascicularis, were used for this study. All experimental procedures as well as animal care and handling adhered to the guidelines outlined in the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. All experimental procedures were also reviewed and approved by an internal institutional review committee for animal use. Ocular Hypertension IOP in the right eye of each animal was elevated using a procedure similar to that originally described by Gaasterland and Kupfer. 1 Briefly, animals were anesthetized with an intramuscular injection of ketamine (15 mg/kg) and topical application of proparacaine (0.5%) in the right eye. Pupillary miosis was induced with instillation of 2.0% pilocarpine. After placement of a goniolens, energy from an argon laser (488 nm ϩ 519 nm, model Novus 2000; Coherent, Inc., Palo Alto, CA) was directed through the anterior chamber to the trabecular meshwork. Individual burns were produced using focused laser spots of 1-W power, 50-m diameter, and 0.5-seconds duration. An initial treatment consisted of 30 to 40 burns applied over the superior 180°of the chamber angle. Two weeks later, the inferior 180°of the trabecular meshwork was similarly treated. IOP was measured in both eyes of each animal at regular intervals under light anesthesia (intramuscular ketamine, 5 mg/kg) using a pneumotonometer (Digilab, Norwell, MA). Electrophysiology ERG recordings were made from both eyes of each animal at approximately 16 months after induction of ocular hypertension. Animals were anesthetized with an intramuscular injection of ketamine (10 mg/kg) in combination with acepromazine (0.5 mg/kg) before placement of an endotracheal tube and intravenous catheter. Instillation of one drop of 1% tropicamide maintained pupil diameter at approximately 6 mm during the recording session. Animals were then positioned in a holder that used soft pressure points and a bite bar t

Glaucoma alters the circadian timing system.

Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN). In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (approximately 50-70%) of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD) cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system