Advantages and uses of the european network of veterinary ophthalmology and animal vision (REOVVA)in pigmentary retinopathies

In pigmentary retinopathies (Retinitis Pigmentosa), an alteration of peripheral vision is associated with a deficit of night vision, followed by a loss of diurnal vision leading to blindness. These diseases are found in both man and dogs, and are characterised by clinical, genetic, cellular and molecular heterogeneity. Therapeutic and rehabilitation strategies for the management of these patients include gene therapy, neuroprotection and retinal prosthesis. Developed in laboratory animals, the therapeutic tools were validated in preclinical trials carried out in dogs. The European Network of Veterinary Ophthalmology and Animal Vision (REOVVA) operates like a centre of clinical investigation combining its skills with those of researchers and physicians from the Institute of Vision, bringing mutual benefits to the treatment of man and animals, the latter being considered as proper patients.Les rétinopathies pigmentaires (Retinitis Pigmentosa) sont des affections caractérisées par une altération de la vision périphérique, associée à un déficit de la vision nocturne et ensuite à une perte de la vision diurne aboutissant à la cécité. Ce sont des maladies homologues au chien et à l'homme caractérisées par une hétérogénéité clinique, génétique, cellulaire et moléculaire. Les stratégies thérapeutiques et réhabilitatrices pour la prise en charge des patients atteints par ces affections font appel à la thérapie génique, la neuro-protection et les prothèses rétiniennes. Mis au point chez l'animal de laboratoire, les outils thérapeutiques ont été validés dans des essais précliniques chez le chien. Considérant le chien comme un véritable patient, le Réseau Européen d'Ophtalmologie Vétérinaire et de Vision Animale (REOVVA) fonctionne comme un centre d'investigation clinique unissant ses compétences avec celles des chercheurs et des médecins de l'Institut de la Vision pour un bénéfice réciproque des traitements de l'homme et de l'animal, considéré comme un patient à part entière

A biophysical model explains the spontaneous bursting behavior in the developing retina

During early development, waves of activity propagate across the retina and play a key role in the proper wiring of the early visual system. During the stage II these waves are triggered by a transient network of neurons, called Starburst Amacrine Cells (SACs), showing a bursting activity which disappears upon further maturation. While several models have attempted to reproduce retinal waves, none of them is able to mimic the rhythmic autonomous bursting of individual SACs and reveal how these cells change their intrinsic properties during development. Here, we introduce a mathematical model, grounded on biophysics, which enables us to reproduce the bursting activity of SACs and to propose a plausible, generic and robust, mechanism that generates it. The core parameters controlling repetitive firing are fast depolarizing $V$-gated calcium channels and hyperpolarizing $V$-gated potassium channels. The quiescent phase of bursting is controlled by a slow after hyperpolarization (sAHP), mediated by calcium-dependent potassium channels. Based on a bifurcation analysis we show how biophysical parameters, regulating calcium and potassium activity, control the spontaneously occurring fast oscillatory activity followed by long refractory periods in individual SACs. We make a testable experimental prediction on the role of voltage-dependent potassium channels on the excitability properties of SACs and on the evolution of this excitability along development. We also propose an explanation on how SACs can exhibit a large variability in their bursting periods, as observed experimentally within a SACs network as well as across different species, yet based on a simple, unique, mechanism. As we discuss, these observations at the cellular level have a deep impact on the retinal waves description.Comment: 25 pages, 13 figures, submitte

Incorporation of chromaffin granule membranes into large-size vesicles suitable for patch-clamp recording

AbstractIncubation of chromaffin granules with excess liposomes at pH 6.0 resulted in the formation of cell-size structures, which were purified by centrifugation on sucrose gradients. Experiments with fluorescein-labeled granules indicated incorporation of granule membrane to these structures. The preparation contained various vesicular structures with a diameter up to 15 μm. The largest elements were studied by the ‘patch-clamp’ technique. ‘Cell-attached’ and ‘whole-cell’ recordings indicated the presence of currents corresponding to unitary conductances ranging from 100 to 500 pS

Photoreceptor degeneration: therapeutic strategies and new perspectives

Ocular diseases involving photoreceptor degeneration still lead to blindness. However, different therapeutic strategies preserving vision have been validated recently, as in age-related macular degeneration (ARMD) or Leber congenital amaurosis (LCA). In the latter, gene therapy was found to restore vision in patients progressively losing eyesight due the loss of their photoreceptors. This major success opened the way for many other forms of gene therapy to prevent blindness or even restore some degree of sight. Optogenetic therapy is one such example, where a gene coding for a photosensitive protein from algae or bacteria is introduced in the genome of a cell to restore some light perception in the blind retina. Other therapeutic strategies rely on trophic factors, such as Ciliary Neurotrophic factor (CNTF) or RdCVF (rod-derived cone viability factor), or calcium channel blockers. Finally, stem cell transplantation is likely to provide new modes of treatment in a near future. These therapeutic strategies therefore hold great promises for diseases leading to blindness and considered as incurable.Les maladies oculaires avec dégénérescence des photorécepteurs sont toujours à l'origine de cécités. Cependant, différentes approches thérapeutiques ont récemment été validées pour préserver la vision, comme dans les cas de la dégénérescence maculaire liée à l'âge ou de l'amaurose congénitale de Leber. Pour cette dernière maladie, la thérapie génique a permis de restaurer la vision de patients perdant progressivement la vue à la suite de la dégénérescence de leurs photorécepteurs. Ce succès majeur a ouvert la voie à de nombreuses autres formes de thérapie génique pour prévenir la cécité ou restaurer une certaine vision par la thérapie optogénétique. Dans ce dernier cas, un gène codant une protéine photosensible issue d'algues ou de bactéries est introduit dans le génome d'une cellule pour restaurer une perception à la lumière dans la rétine aveugle. D'autres approches thérapeutiques reposent sur les facteurs trophiques comme le CNTF (ciliary neurotrophic factor) ou le RdCVF (rod-derived cone viability factor), ou encore les inhibiteurs des canaux Ca2+. Enfin, la transplantation de cellules souches est amenée à devenir un mode thérapeutique dans un futur proche. Ces différentes approches offrent donc un grand espoir de traitement des maladies entraînant la cécité et considérées comme incurables

Eye and taurine

Taurine is the most abundant amino acid in retina. Although unclear, its role is mainly related to its powerful antioxidant properties. The taurine concentrations in tissues are regulated by an exogenous intake through the nutrition. This taurine intake is highly dependent on the function of taurine transporter. In addition, an endogenous synthesis accounts for the physiological taurine amounts. Previous studies had shown that taurine nutritional deprivation in cat was responsible for severe retinal damages at the photoreceptor layer. By discovering the taurine depletion was incriminated in the retinal toxicity of vigabatrin, we recently demonstrated in different models of retinal degeneration that taurine was involved in the retinal ganglion cells survival. Accordingly, Taurine may play a crucial role in the prevention of retinal degeneration such as retinopathies and glaucomas.La taurine est l’acide aminé le plus abondant dans la rétine. Son rôle, encore mal connu est essentiellement lié à son pouvoir anti-oxydant. Sa concentration tissulaire dépend d’un apport nutritionnel en taurine exogène et du fonctionnement de son transporteur. De plus, une synthèse endogène de taurine participe au maintien de son taux physiologique. D’anciennes études ont montré que la privation nutritionnelle de taurine chez le chat est responsable de dommages rétiniens graves, affectant la couche des photorécepteurs. En découvrant que la toxicité du vigabatrin est liée à une déplétion en taurine, nous avons récemment montré que la taurine participe également à la survie des cellules ganglionnaires rétiniennes dans différents modèles de dégénérescence rétinienne. La taurine pourrait ainsi être impliquée dans la prévention des dégénérescences rétiniennes telles que les rétinopathies et les glaucomes

Modeling the emergence of stage II retinal waves in immature retina

International audienceRetinal waves are spontaneous bursting activity propagating in the developping retina until vision is functional. In this work we propose a biophysical modelling of the mechanism that generates the spontaneous intrinsic cell-autonomous rhythmic bursting in Starbust Amacrine Cells (SACs), observed experimentally in [1] which is directly linked with the emergence of stage II retinal waves. We analyze this system from the dynamical system and bifurcation theory perspective

Pattern formation and criticality in the developing retina

International audienceIn the early retina, spontaneous collective network activity emerges as propagating waves, playing a central role in shaping the visual system. Elucidating how the characteristics of such waves depend on biophysical parameters, would help us understand the underlying mechanisms of spatio-temporal patterns formation in the developing retina and their role in shaping the visual system. We have elaborated a set of detailed biophysical equations for a network of retinal cells coupled with excita-tory lateral cholinergic connections, close enough to reality to reproduce and predict experimental results. From bifurcation theory, we predict that there exists a regime of parameters for which the network of cells in the developing retina is a critical system. This property is manifested via power law distributions for the waves characteristics (i.e. waves size), meaning that waves statistics could exhibit maximal variability. This critical regime is analytically characterized, predicting the exact form of the critical coupling strength of cells. Away from this regime of parameters, no power-law like distributions are observed. This theoretical result is in agreement with our experimental recordings in perinatal mice, revealing power-laws as well, suggesting that there exists a mechanism setting the retinal cells close to this critical regime. Context & Motivation Retinal waves characteristics exhibit a vast variability: Questions: 1. How do the variable characteristics of retinal waves depend on few biophysical parameters? 2. How can we characterize quantitatively the different dynamical regimes and the transitions between them? 3. Why is it important for the early retinal network to exhibit large variability in the characteristics of spatiotemporal patterns? 4. What are the biophysical mechanisms of the spatiotemporal patterns formation in the early retina? Patterns vary upon parameters variation Having proposed a biophysical model for retinal waves [1], we use our equations to understand the underlying mechanisms of waves apparition and propagation: Analytic condition for wave propagation Waves propagation analytic condition for a critical threshold of cholinergic coupling Based on bifurcation theory: 1. We derive analytic forms for a critical waves propagation threshold of coupling strength among cells g A C , and for the waves speed (not shown). 2. We propose a possible mechanism of how power-law distributions could appear near this propagation threshold, where the cell is in fact close to a (saddle-node) bifurcation point. At this point, dynamics are driven mainly by noise fluctuations, leading to maximum variance in the patterns characteristics (e.g. waves size), manifesting power-law like distributions, and therefore indicating possible links to criticality. Finding power-laws in experiments We performed MEA (256 electrodes) experiments on P5 mice (stage II retinal waves) at Vision Institute, Paris. • A power-law distribution for the waves size is computed at the regime where the transition occurs in our model (B), matching our experimental data on P5 mice. • This indicates that maybe the network of SACs is naturally set close to a critical state by a possible homeostatic mechanism, yet to be identified. Conclusions and Perspectives • Our model allows us to anticipate how biophysical parameters variations (e.g. conductance) may impact the characteristics of waves. • We predict that SACs are close to a bifurcation point, leading to explaining the different types of variability of retinal waves as well as proposing encouraging, although still primary links to criticality. • Further analysis is needed to characterize critical systems, such as studying in detail possible phase transitions, and computing critical exponents on the theoretical side. • On the experimental side, new and more precise methods should be proposed for the exact characterization of power-law distributions in experimental recordings. • Extend our phenomenological model in order to identify the possible homestatic mechanism that drives the network to a critical state. • Explore the role of the indicated criticality in the early retina, possibly related to an optimizing the response sensitivity to multi-scale stimuli upon matura-tion, enhancing the dynamical range of the early network (Steven's law)

Ion channels and properties of large neuronal networks: a computational study of re.nal waves during development

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