Retinal remodeling in the Tg P347L rabbit, a large‐eye model of retinal degeneration

Jones, Bryan W.; Kondo, Mineo; Terasaki, Hiroko; Watt, Carl B.; Rapp, K.; Anderson, James R.; Lin, Yuan; Shaw, Marguerite Victoria; Yang, Jian; Marc, Robert E.

doi:10.1002/cne.22703

Cited by 87 publications

(104 citation statements)

References 90 publications

(199 reference statements)

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“…Our serial section analysis showed that more than half the metabolites that we measure from whole-retina homogenates comes from the photoreceptor layer, consistent with other studies that used a different type of method to map distributions of amino acids in retina (15,16). However, the experimental approach we used in our study does not distinguish the metabolites from photoreceptors from the metabolites from other neurons and from glia.…”

Section: Discussionsupporting

confidence: 87%

Cytosolic reducing power preserves glutamate in retina

Du¹,

Cleghorn²,

Contreras

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Glutamate in neurons is an important excitatory neurotransmitter, but it also is a key metabolite. We investigated how glutamate in a neural tissue is protected from catabolism. Flux analysis using 13 C-labeled fuels revealed that retinas use activities of the malate aspartate shuttle to protect >98% of their glutamate from oxidation in mitochondria. Isolation of glutamate from the oxidative pathway relies on cytosolic NADH/NAD + , which is influenced by extracellular glucose, lactate, and pyruvate. G lutamate is especially important as a metabolite because it is required for the synthesis of glutathione, other amino acids, and proteins. Glutamate also is a key intermediate in glutaminedependent anaplerosis, now known to be a principal source of citric acid cycle intermediates in cancer cells (1).When it is released as a neurotransmitter at brain synapses, glutamate that escapes from the synapse is taken up by astrocytes. There it is converted to glutamine and is delivered back to neurons in a process called the "glutamate/glutamine cycle" (2). Uptake of glutamate and conversion to glutamine within astrocytes stimulates glycolysis and synthesis of lactate. Astrocytes export the lactate to neurons as fuel in a process called the "astrocyte neuron lactate shuttle" (ANLS) (3).Synaptic terminals of rod and cone photoreceptors have characteristics that appear incompatible with the ANLS. The photoreceptor terminal is enriched with transporters for reuptake of glutamate (4), and it encapsulates the synapse. It is unlikely that much glutamate can escape the synapse before being sequestered back into the photoreceptor. We initiated a study to evaluate the role of ANLS in retina. However, the unusual metabolic features of retina revealed a surprising feature of neuronal metabolism, that >98% of glutamate is protected from catabolism. We investigated this protection and show here that the protection is provided by activities associated with the metabolic pathway known as the "malate aspartate shuttle" (MAS) (shown schematically in Fig. 1).MAS activity regenerates cytosolic NAD + that is needed to support glycolysis. To do so, it uses two important transporters to trap the reducing power from cytosolic NADH and shuttle it into the mitochondrial matrix. One transporter is the neuronal aspartate/glutamate carrier (AGC1 or Aralar) (Fig. 1, orange circle); the other transporter is the oxoglutarate carrier (OGC) (Fig. 1, light blue circle). AGC1 transports glutamate from the cytoplasm into the mitochondrial matrix in exchange for aspartate from the matrix (Fig. 1). OGC transports α-ketoglutarate from the matrix into the cytoplasm in exchange for malate from the cytoplasm (Fig. 1) (5). An important consequence of MAS activity is that it diverts metabolic flux in mitochondria away from succinyl CoA, succinate, and fumarate (Fig. 1). Most importantly, glutamate that completes a MAS cycle functions as a catalyst for the importation of reducing power into the mitochondria. The carbon atoms of glutamate are isolated from the oxidative...

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Section: Discussionsupporting

confidence: 87%

Cytosolic reducing power preserves glutamate in retina

Du¹,

Cleghorn²,

Contreras

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 90%

“…17 We also found that the rod bipolar cells effectively lose rod contacts and make ectopic cone contacts and express iGluRs. 17 This secondary retinal remodeling may contribute to the enhanced post-photoreceptoral responses in our Tg rabbits. Similarly, detailed ERG studies in rhodopsin P347L Tg pigs and rabbits have demonstrated that the electrical activities of the cone ON-pathway were also enhanced at a relatively early stage of retinal degeneration.…”

Section: Discussionmentioning

confidence: 90%

Photoreceptor and Post-Photoreceptoral Contributions to Photopic ERG a-Wave in Rhodopsin P347L Transgenic Rabbits

Hirota

Kondo

Ueno

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.The a-wave of the photopic electroretinogram (ERG) of macaque monkeys is made up of the electrical activities of cone photoreceptors and post-photoreceptoral neurons. However, it is not known whether the contributions of these two components change in retinas with inherited photoreceptor degeneration. The purpose of this study was to determine the contributions of cones and post-photoreceptoral neurons to the a-wave of the photopic ERGs in rhodopsin Pro347Leu transgenic (Tg) rabbits. METHODS. Ten Tg and 10 wild-type (WT) New Zealand White rabbits were studied at 4 and 12 months of age. The a-waves of the photopic ERGs were elicited by xenon flashes of different stimulus strengths before and after the activities of post-photoreceptoral neurons were blocked by intravitreal injections of a combination of 0.2 to 0.4 mM of 6-cyano-7-nitrouinoxaline-2,3(1H,4H)-dione, disodium (CNQX) and 2 to 4 mM of (Ϯ)-2-amino-4-phosphonobutyric acid. RESULTS. The percentage contribution of the cone photoreceptors to the photopic ERG a-waves increased with increasing stimulus strength, and the percentage ranged from 54% to 75% in 4-month-old WT rabbits. In contrast, the percentage contribution of the cone photoreceptors in 4-month-old Tg rabbits ranged from 32% to 51% (P Ͻ 0.05). The mean percentage contribution of cone photoreceptors became still smaller at 11% to 48% in 12-month-old Tg rabbits. CONCLUSIONS. These results suggest that the relative contribution of cone photoreceptors to the photopic ERG a-wave is smaller in retinas with inherited photoreceptor degeneration. This indicates that the a-waves of the photopic ERGs in patients with retinitis pigmentosa must consider this lower contribution from the cone photoreceptors. (Invest Ophthalmol Vis Sci. 2012;53:1467-1472 The origins of the photopic or light-adapted a-wave of the ERG in macaque monkeys was studied by Sieving et al.3-5 They injected glutamate agonists and antagonists intravitreally to dissect the retinal circuits. They found that the a-wave of the photopic ERG received contributions not only from the cone photoreceptors but also from post-photoreceptoral neurons (e.g., OFF-bipolar cells and horizontal cells) 3,4 because cis-2,3-piperidine dicarboxylic acid (PDA) or kynurenic acid reduced the a-wave amplitude. A later study by Robson et al. 6 showed that the PDA-sensitive post-photoreceptoral a-wave component started at much earlier times of approximately 5 ms in macaques. Frieberg et al.7 also estimated the time course of the cone photoreceptor response in normal human ERGs using the paired-flash technique, in which an intense "probe" flash was delivered at different times after a "test" flash. Their results showed that the photopic ERG a-wave of the human ERG contains an appreciable postphotoreceptoral component, similar to that reported in monkeys. [3][4][5][6] These studies, which were designed to determine the origins of the photopic ERG a-wave, have been performed primarily on normal macaque monkeys and human eyes.3-7 It is not known whether the contr...

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“…Electron Microscopy-Isolated mouse eyecups were fixed by immersion in fixative solution (2% glutaraldehyde, 1% paraformaldehyde in 0.1 M cacodylate buffer, pH 7.4) at 4°C overnight (32,46). The eyecups were then postfixed with 1% osmium tetroxide in 0.1 M cacodylate for 1 h, buffer-rinsed, stained en bloc with uranyl acetate, and subsequently dehydrated in an ascending series of methanol solutions.…”

Section: Mice-kif3amentioning

confidence: 99%

Heterotrimeric Kinesin-2 (KIF3) Mediates Transition Zone and Axoneme Formation of Mouse Photoreceptors

Jiang

Wei

Ronquillo

et al. 2015

Journal of Biological Chemistry

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Background: Heterotrimeric kinesin-2 (KIF3) has been implicated in intraflagellar trafficking of photoreceptor membrane proteins by IFT. Results: KIF3 and IFT88 are required for transition zone and axoneme formation, but are dispensable for rhodopsin trafficking. Conclusion: Transmembrane proteins, including rhodopsin, traffic to the OS even when IFT is disabled. Significance: KIF3 builds and maintains the photoreceptor transition zone and axoneme that are essential for photoreceptor integrity and vision.

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Retinal remodeling in the Tg P347L rabbit, a large‐eye model of retinal degeneration

Cited by 87 publications

References 90 publications

Cytosolic reducing power preserves glutamate in retina

Cytosolic reducing power preserves glutamate in retina

Photoreceptor and Post-Photoreceptoral Contributions to Photopic ERG a-Wave in Rhodopsin P347L Transgenic Rabbits

Heterotrimeric Kinesin-2 (KIF3) Mediates Transition Zone and Axoneme Formation of Mouse Photoreceptors

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