La cianotoxina β-N-metil-amino-L-alanina (BMAA) es un aminoácido no proteico producido por cianobacterias, capaz de biomagnificarse en las cadenas tróficas de ecosistemas marinos y terrestres. Dada su capacidad de atravesar la barrera hematoencefálica, su ingesta progresiva se asocia con el desarrollo de ciertas retinopatías, así como también de enfermedades neurodegenerativas, tales como la Esclerosis Lateral Amiotrófica (ELA), la Enfermedad de Parkinson (EP) y la Enfermedad de Alzheimer (EA). Los daños causados por la BMAA son múltiples y originados en mecanismos diversos. Así, la BMAA, en presencia de iones bicarbonato (HCO3 - ), puede formar un compuesto denominado carbamato, cuya estructura química es similar al glutamato (Glut), uno de los neurotransmisores más importantes del sistema nervioso. A su vez, el carbamato se une y activa receptores de Glut, ya sean ionotrópicos (como el receptor de N-metil-D- aspartato) o metabotrópicos. La sobreexcitación de estos receptores ocasionada por la BMAA, promueve mecanismos de excitotoxicidad que conducen a alteraciones neuronales. Por otro lado, la BMAA puede ingresar a las células a través del sistema xc, un sistema de transporte sodio-independiente común para cistina y Glut. Una vez en el interior celular, la toxina puede incorporarse erróneamente en las cadenas polipeptídicas en reemplazo de Serina (Ser). Así, unida a componentes proteicos, puede generar un reservorio endógeno de lenta liberación que expone a las neuronas a una baja pero continua dosis de esta toxina. Entre sus varios efectos subcelulares, la BMAA puede afectar la permeabilidad de las membranas mitocondriales comprometiendo su actividad. Además, puede inducir modificaciones en los niveles de Ca 2+, generar estrés oxidativo, promover fallas en la producción de ATP e inducir estrés en el retículo endoplasmático, lo cual conduce a alteraciones en la síntesis y/o distribución de proteínas. Asociado a esto, se originan alteraciones en el transporte axonal y la fragmentación de estas estructuras. Pese a su trascendencia para la salud, aún son desconocidos los efectos directos que genera la exposición a la BMAA de las neuronas y células gliales de la retina (como las células gliales de Müller –CGM-), o del epitelio pigmentario de la retina (EPR). Además, todavía son mayormente desconocidos aquellos factores o moléculas capaces de modular las vías de señalización involucradas en los efectos deletéreos inducidos por la BMAA. Al respecto, recientemente se ha propuesto que la activación de los receptores X retinoides (RXR) protegerían a las neuronas y modularían la respuesta inflamatoria durante las enfermedades neurodegenerativas del sistema nervioso central, y también en retinopatías. Aún se desconoce si estos receptores ejercen un rol protector contra los daños inducidos por la BMAA. En esta Tesis se estudiaron los mecanismos involucrados en los cambios degenerativos inducidos por la BMAA en células de la retina, así como también en células PC12 diferenciadas a neuronas. Asimismo, se evaluó el valor protector de agonistas de los RXRs frente a los efectos deletéreos inducidos por la BMAA en células de la retina. Para estos estudios, se obtuvieron cultivos puros de neuronas amacrinas y fotorreceptores (FRs), de CGM puros, y cultivos neuro-gliales a partir de retinas de ratas neonatas. Además, se utilizaron cultivos de líneas celulares PC12 y epiteliales ARPE- 19. Todos los cuales fueron tratados con la BMAA para evaluar sus efectos sobre estas células y el posible rol protector de los RXRs. Los resultados obtenidos en este trabajo demostraron que aún bajas concentraciones de la BMAA (de 0,4 μM) alteraron la viabilidad no sólo de las neuronas amacrinas y FRs, sino también de las células PC12 diferenciadas a neuronas, de las CGM e incluso de las células del EPR. La BMAA también, indujo alteraciones en la permeabilidad mitocondrial y en la producción de ROS en las células neuronales, gliales y epiteliales, mientras que en las CGM indujo cambios en la morfología nuclear. Por su parte, en neuronas amacrinas, promovió el crecimiento axonal, aunque generando el colapso de sus conos de crecimiento. Estas alteraciones fueron mediadas por la activación de los receptores NMDA en presencia de iones HCO3 - . Además, en estas células, la BMAA se incorporaría erróneamente en las cadenas polipeptídicas en reemplazo de la Ser, dado que la suplementación del medio de cultivo con este aminoácido previno la toxicidad inducida por la BMAA. En cuanto a la acción protectora de los RXRs, nuestros resultados demostraron que su activación bloqueó los efectos tóxicos que produjo la BMAA sobre las neuronas amacrinas y los FRs, así como también sobre las células del EPR. En resumen, en esta Tesis presentamos evidencias de que la BMAA afecta múltiples estructuras subcelulares en las células que conforman la retina, así como también a células PC12 diferenciadas. Estos resultados sugieren que los daños inducidos por la BMAA representan un potencial riesgo para la salud, y podrían contribuir al desarrollo de retinopatías, así como de varias enfermedades neurodegenerativas. Además, este trabajo indicaría que la activación de los RXRs puede presentar un papel protector al ejercer un rol relevante en la supervivencia de las neuronas amacrinas y FRs, así como también de las células del EPR. En su conjunto, estos hallazgos aportan nuevos conocimientos en relación a los mecanismos deletéreos inducidos por la BMAA y podrían ser de utilidad para el desarrollo de futuras estrategias terapéuticas. / The cyanotoxin β–N-methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by cyanobacteria. It is biomagnified along the food chains in both, marine and terrestrial ecosystems. Due to its ability to cross the brain blood barrier, its ingestion may contribute to the onset of retinopathies, as well as neurodegenerative diseases, like Amyotrophic Lateral Sclerosis, Parkinson (PD) and Alzheimer disease (AD). Damages induced by BMAA are multiple and originated by different mechanisms. In the presence of bicarbonate ions (HCO3 - ), BMAA can produce carbamate, whose chemical structure is similar to that of glutamate (Glut), one of the most important neurotransmitters in the nervous system. In turn, carbamate can bind and activate both ionotropic (like N-Methyl-D-aspartate -NMDA-) and metabotropic Glut receptors. Overactivation of these receptors by BMAA promotes excitotoxicity, which leads to nuclear alterations. On the other hand, BMAA crosses the cell membranes by using the cystine/glutamate antiporter (xc- system), a sodium-independent amino acid transporter. Once inside the cells, the toxin can mistakenly replace the amino acid Serine (Ser) in polypeptide chains, thus generating an endogenous reservoir of BMAA, whose slow- release exposes neurons to a low, but continuous amount of this toxin. Among its various subcellular effects, BMAA can alter mitochondrial membrane permeability compromising mitochondrial activity. Besides, it can alter Ca2+ levels, generate oxidative stress, promote failures in the ATP production and induce endoplasmic reticulum (RE) stress, leading to alterations in the protein synthesis and/or distribution. In this context, BMAA promotes alterations in axonal transport along with fragmentation of these structures. Despite its importance to health, the direct effects of BMAA exposure on retinal neurons and glial cells (such as Müller glial cells –CGM-), or retinal pigment epithelium (RPE) cells, are virtually unknown and the factors or molecules, which could modulate the signaling pathways involved in the deleterious effects induced by BMAA have not been established. In this regard, it has recently been proposed that the activation of Retinoid X Receptors (RXR) can protect neurons and modulate the inflammatory responses during neurodegenerative diseases of the central nervous system, including retinopathies. However, the possible protective roles of RXRs in BMAA-induced damages are still unknown. In this Thesis, we have studied the mechanisms involved in the degenerative changes induced by BMAA into retinal cells, and in neuron-like, differentiated rat pheochromocytoma cells (PC12 cells), as well. We also evaluated the protection of RXR agonists against the deleterious effects of BMAA in retinal cells. For these purposes, we obtained pure neuronal cultures of amacrine neurons and photoreceptors (PHRs); pure MGC cultures, and mixed neuro-glial cultures from newborn rats. In addition, we used PC12 cells and ARPE-19 epithelial cell lines. We treated them with BMAA to evaluate its effects on these cells and the possible protective roles of RXRs. Our results showed that low concentrations of BMAA (0.4 μM) altered, not only the viability of amacrine neurons and PHRs, but also that of neuronally differentiated PC12 cells, MGC and even that of the RPE cells. Also, the cyanotoxin induced alterations in mitochondrial membrane permeability and in ROS production, while in MGC, BMAA induced changes in the nuclear morphology. On the other hand, in amacrine neurons, this toxin promoted axonal growth, although simultaneously generating the collapse of their growth cones. We established that all these alterations were induced by activation of NMDA receptors in the presence of HCO3 - ions. Besides, in all these cell types, BMAA appeared to incorporate into polypeptide chains replacing Ser, since supplementation of the culture media with this amino acid prevented toxicity damages. Regarding the protective roles of RXRs, our results showed that their activation blocked the toxic effects induced by BMAA in amacrine neurons, PHRs, and RPE cells. In summary, in this Thesis we present evidences that BMAA affected multiple subcellular structures in retina cells and in PC12 cells differentiated into neurons. These results suggest that the damaging effects induced by BMAA represent a potential health risk, which could contribute to the development of retinopathies, along with other neurodegenerative diseases. In addition, this work would indicate that RXR activation can promote survival of amacrine PHRs and RPE cells. Taken together, these findings provide new knowledge regarding the deleterious mechanisms induced by BMAA, which could be useful for the development of future effective therapies.

La Retinitis Pigmentaria (RP) y la Degeneración Macular Asociada a la Edad (AMD) son enfermedades neurodegenerativas de la retina que se caracterizan por la pérdida progresiva e irreversible de las neuronas fotorreceptoras (FR). Ambas enfermedades son incurables, conducen a la pérdida de visión y no cuentan con tratamientos efectivos. Una estrategia para lograr desarrollar una terapia más adecuada para estas enfermedades es la utilización de células madre que puedan restaurar los tejidos dañados. Sin embargo, regenerar la retina requiere resolver varios problemas poco explorados: uno de ellos es la escasa actividad regenerativa de las células gliales de Müller (CGM) de la retina que, si bien han sido propuestas como células madre, poseen una efectividad muy limitada en mamíferos y son ineficientes para recuperar los FR perdidos. Otro problema es la respuesta reactiva de las CGM, la cual ocurre luego de daños en la retina y genera una inflamación crónica local que afecta la supervivencia de las neuronas regeneradas. Al respecto, recientemente se ha propuesto que los receptores X para retinoideos (RXR) son moduladores de la respuesta inflamatoria que protegerían a las neuronas durante las enfermedades neurodegenerativas del SNC. Sin embargo, aún se conoce muy poco sobre su rol en la retina. El estudio de estas enfermedades enfrenta dificultades éticas y prácticas, por lo que el uso de ratones rd1, un modelo animal de RP que presenta una mutación específica que causa la muerte por apoptosis de los FR, resulta extremadamente útil para investigar las causas de la escasa capacidad regenerativa de la retina. Con este objetivo utilizamos retinas enteras y cultivos primarios neuronales y de CGM de ratones control y rd1. También investigamos y comparamos la actividad proliferativa de las CGM y la expresión de diversos marcadores de células madre, así como la expresión de los RXR y su efectos sobre la supervivencia neuronal y reactividad glial ante el tratamiento con un agonista sintético de estos receptores. Los resultados indicaron una disminución de los marcadores de célula madre de las CGM rd1. Notablemente, la expresión de uno de ellos, Nestina, pudo ser revertida al co-cultivar las CGM rd1 con neuronas control (wt), lo que sugiere una alteración en la comunicación neuro-glial. Además, el agonista sintético de los RXR, PA024, retrasó la muerte de los FR y disminuyó la reactividad glial en cultivos de retinas rd1. En resumen, en esta tesis presentamos evidencia de que en las retinas rd1 existe una alteración en la comunicación neuro-glial que afectaría el potencial regenerativo y dispararía una respuesta reactiva en las CGM. Asimismo, hallamos que la reactividad de las CGM y la muerte de los FR en las retinas rd1 pudo ser disminuida mediante la utilización de un agonista de los RXR. Estos resultados sugieren que el potencial regenerativo de las CGM dependería de su interacción con neuronas sanas; que durante los procesos neurodegenerativos de la retina este diálogo neuro-glial estaría afectado; y que los RXR regularían, en parte, los procesos inflamatorios y la supervivencia neuronal en la retina. Estos hallazgos podrían ser de utilidad para el desarrollo de una terapia efectiva de reemplazo celular. / Retinitis Pigmentosa (RP) and Age-related Macular Degeneration (AMD) are neurodegenerative diseases of the retina which are characterized by the progressive and irreversible loss of photoreceptor neurons (PRs). Both diseases are incurable, lead to loss of vision and lack effective treatment. A strategy to develop an adequate therapy involves the use of stem cells that are able to restore damaged tissue. However, retina regeneration requires solving many unexplored issues. One of them is poor regenerative activity of Müller glial cells (MGC) of the retina. Although these cells have been postulated as stem cells, they have limited effectiveness in mammals and are inefficient to recover lost PRs. Another issue is the reactive response of MGC, which occurs after damage to the retina and causes local chronic inflammation that affects the survival of regenerated neurons. In that regard, it has recently been claimed that retinoid X receptors (RXR) are inflammatory response modulators that could protect the neurons from neurodegenerative diseases of the central nervous system. However, little is known about the role they play in the retina. Research into these diseases faces many ethical and practical challenges. Therefore, using rd1 mice, an animal model of RP with a very specific mutation which causes death by apoptosis of PRs, is extremely useful to study the causes of poor regenerative capacity of the retina. For this purpose, we have used whole retinas and primary neural and MGC cultures from control and rd1 mice. We have also studied and compared the proliferative activity of MGC and the expression of several stem cell markers, as well as the expression of RXR and their effect on neuronal survival and glial reactivity upon treatment with a synthetic agonist. Results showed decreased rd1 MGC stem cell markers. Remarkably, the expression of one of these, Nestin, could be reverted by co-culturing of rd1 MGC with control neurons (wt), which suggests an alteration in neuroglial communication. Furthermore, using the RXR synthetic agonist PA024 delayed death of PRs and decreased glial reactivity in rd1 retina cultures. In sum, throughout this thesis we have presented evidence that in rd1 retinas there is an alteration in neuroglial communication which could affect the regenerative potential and trigger a reactive response of MGC. Additionally, we found that MGC reactivity and death of PRs in rd1 retinas could be reduced by means of a RXR agonist. These results suggest that regenerative potential of MGC could depend on their interaction with healthy neurons, that neuroglial communication could be affected when neurodegenerative processes of the retina take place, and that RXR could partially regulate inflammatory processes and neuronal survival in the retina. These findings could prove useful for the development of an effective cellular replacement therapy.

Estudamos a Torção Analítica para variedades com bordo e ainda com singuaridades do tipo cônico, mais especificamente, para um cone métrico limitado, com o propósito de investigar a extensão natural do Teorema de Cheeger Müller para tais espaços. Começamos determinando a Torção Analítica do disco e de variedades com o bordo totalmente geodésico, por meio de ferramentas geométricas desenvolvidas por J. Brüning e X. Ma. Posteriormente, usando ferramentas analíticas desenvolvidas por M. Spreafico, determinamos a Torção Analítica do cone sobre uma esfera de dimensão ímpar e provamos um teorema do tipo Cheeger Müller para este espaço. Mais ainda, provamos que o resualto de J. Brüning e X. Ma estende para o cone sobre uma esfera de dimensão ímpar / We study for Analytic Torsion of manifolds with boundary and also with conical singularities , more specifically, for a finite metric cone, with the purpose of investing the natural extension of the Cheeger Müller theorem for such spaces. we start by computing the Analytic Torsion of an any dimensional disc and of a manifold with totally boundary, by using geometric tools development by J. Brüning and X. Ma. Then, by using analytic tools development by M. Spreafico, we determine the Analytic Torsion of a cone over an odd dimensional sphere and we prove a theorem of Cheeger Müller type space. Moreover, we prove that the result of J. Brüning and X. Ma extends to the cone over an odd dimensional sphere

Estudamos a Torção Analítica para variedades com bordo e ainda com singuaridades do tipo cônico, mais especificamente, para um cone métrico limitado, com o propósito de investigar a extensão natural do Teorema de Cheeger Müller para tais espaços. Começamos determinando a Torção Analítica do disco e de variedades com o bordo totalmente geodésico, por meio de ferramentas geométricas desenvolvidas por J. Brüning e X. Ma. Posteriormente, usando ferramentas analíticas desenvolvidas por M. Spreafico, determinamos a Torção Analítica do cone sobre uma esfera de dimensão ímpar e provamos um teorema do tipo Cheeger Müller para este espaço. Mais ainda, provamos que o resualto de J. Brüning e X. Ma estende para o cone sobre uma esfera de dimensão ímpar / We study for Analytic Torsion of manifolds with boundary and also with conical singularities , more specifically, for a finite metric cone, with the purpose of investing the natural extension of the Cheeger Müller theorem for such spaces. we start by computing the Analytic Torsion of an any dimensional disc and of a manifold with totally boundary, by using geometric tools development by J. Brüning and X. Ma. Then, by using analytic tools development by M. Spreafico, we determine the Analytic Torsion of a cone over an odd dimensional sphere and we prove a theorem of Cheeger Müller type space. Moreover, we prove that the result of J. Brüning and X. Ma extends to the cone over an odd dimensional sphere

Dans la rétine, la protéine dystrophine Dp71 est principalement exprimée dans les cellules gliales de Müller (CGM), qui contribuent à la stabilisation de la barrière hémato-rétinienne (BHR). Les CGM sont aussi les principales sources de facteurs inflammatoires. Ainsi, nous avons étudié les effets de l’absence de Dp71 sur l’homéostasie potassique et aqueuse, ainsi que sur l’expression de médiateurs de l’inflammation et la perméabilité vasculaire rétinienne.L'absence de Dp71 diminue l'expression de la protéine AQP4 et induit la redistribution de Kir4.1 tout le long des CGM. Par ailleurs, nous avons également constaté que le décollement expérimental de la rétine chez les souris WT induit une diminution de Dp71 associée à une délocalisation de Kir4.1, une régulation à la baisse de la protéine AQP4 dans les CGM.Nos données montrent clairement que l'absence de la Dp71 entraîne une augmentation de l'expression du VEGF, d’ICAM-1, une augmentation du nombre de leucocytes adhérents rétiniens, une dégénérescence accrue des capillaires associée à une forte perméabilité vasculaire chez les souris Dp71-null.L’ensemble de nos résultats a mis en évidence le rôle de la Dp71 dans les mécanismes visant à réguler l'homéostasie rétinienne et à assurer la stabilisation de la BHR. Nous apportons la preuve que la perte de Dp71 favorise l'inflammation vasculaire rétinienne et la dégénérescence des capillaires associée à une perméabilité vasculaire. Ensemble, ces observations suggèrent que la souris Dp71-null serait un modèle approprié pour étudier les pathologies vasculaires rétiniennes telles que la rétinopathie diabétique, l’uvéite rétinienne et l’occlusion veineuse rétinienne. / In the retina, the Dp71 dystrophin protein is mainly expressed in Müller glial cells (MGC), which contribute to the stabilization of the blood-retinal barrier (BRB). MGC are also the main sources of inflammatory factors. Thus, in our thesis project we studied the effects of the absence of the Dp71 protein on potassium and water homeostasis, as well as the expression of inflammatory mediators and retinal vascular permeability.The absence of the Dp71 protein decreased the expression of AQP4 protein and induces the redistribution of Kir4.1, initially restricted to the end-feet of MGC and around vessels, all along the cell membrane. Moreover, we have also shown that the experimental retinal detachment in WT mice induces a reduction of Dp71 which is associated with Kir4.1 mislocation, a down regulation of AQP4 protein in MGC.Our data clearly demonstrate that the absence of the Dp71 leads to increased retinal VEGF and ICAM-1 expression in Dp71-null mouse compared to WT mouse strain. There is also an increase of the number of retinal adherent leukocytes, capillary degeneration associated with high BRB permeability observed in Dp71-null mice.Our findings highlight Dp71 as an important component in the mechanisms leading to the regulation of retinal homeostasis; and to the maintaining of the BRB stabilization. We provide evidence that deficiency of Dp71 promotes retinal vascular inflammation and significantly exacerbated degeneration of capillaries and BRB breakdown. Together these results suggest that the Dp71-null mouse could be a good model to study retinal vascular diseases such as diabetic retinopathy, retinal uveitis and retinal vein occlusion.

(anglicky) This dissertation joins a conversation in German literary studies about East German literature's role, identity, and characteristic features. The thesis discusses the phenomenon of autonomy of the dramatic compositions written by Peter Hacks and Heiner Müller in the 1960s and 1970s in the GDR. The theoretic background of the research consists, among other things, of a short introduction to theoretical concepts developed by Kenneth Burke (particularly his New Rhetoric approach presented in The philosophy of literary form), Raymond Williams (including his cultural materialism), as well as Max Horkheimer and Theodor Adorno (Critical Theory). Furthermore, the dissertation deals with the idea of metatheatre, and it discusses elements of metadrama (Karin Vieweg-Marks) in the selected plays. The symbolic boundaries of research are the Berlin Wall's construction in 1961 and the expulsion of the German poet and songwriter Wolf Biermann in 1976. By analyzing the authors' concrete strategies, the thesis demonstrates that their plays articulate both the European literary tradition and the (East) German socialist project.

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Müller cells are major glial cells in the retina and have a broad range of functions that are vital for the retinal neurons. During retinal injury gliotic response either leads to Müller cell dedifferentiation and formation of a retinal progenitor or to maintenance of mature Müller cell functions. The overall aim of this thesis was to investigate the intra- and extracellular signaling of Müller cells, to understand how Müller cells communicate during an injury and how their properties can be regulated after injury. Focus has been on the α2-adrenergic receptor (α2-ADR) and endothelin receptor (EDNR)-induced modulation of Müller cell-properties after injury. The results show that α2-ADR stimulation by brimonidine (BMD) triggers Src-kinase mediated ligand-dependent and ligand-independent transactivation of epidermal growth factor receptor (EGFR) in both chicken and human Müller cells. The effects of this transactivation in injured retina attenuate injury-induced activation and dedifferentiation of Müller cells by attenuating injury-induced ERK signaling. The attenuation was concomitant with a synergistic up-regulation of negative ERK- and RTK-feedback regulators during injury. The data suggest that adrenergic stress-signals modulate glial responses during retinal injury and that α2-ADR pharmacology can be used to modulate glial injury-response. We studied the effects of this attenuation of Müller cell dedifferentiation on injured retina from the perspective of neuroprotection. We analyzed retinal ganglion cell (RGC) survival after α2-ADR stimulation of excitotoxically injured chicken retina and our results show that α2-ADR stimulation protects RGCs against the excitotoxic injury. We propose that α2-ADR-induced protection of RGCs in injured retina is due to enhancing the attenuation of the glial injury response and to sustaining mature glial functions. Moreover, we studied endothelin-induced intracellular signaling in Müller cells and our results show that stimulation of EDNRB transactivates EGFR in Müller cells in a similar way as seen after α2-ADR stimulation. These results outline a mechanism of how injury-induced endothelins may modulate the gliotic responses of Müller cells. The results obtained in this thesis are pivotal and provide new insights into glial functions, thereby uncovering possibilities to target Müller cells by designing neuroprotective treatments of retinal degenerative diseases or acute retinal injury.

La formation et l’intégrité de la barrière hémato-rétinienne (BHR) sont nécessaires au maintien d’une bonne vision et la violation de cette barrière contribue à l’apparition d’un grand nombre de pathologies rétiniennes tel que la rétinopathie diabétique (RD) ou l’occlusion de la veine centrale de la rétine (OVCR). La dystrophine Dp71 est une protéine du cytosquelette associée à la membrane qui s’exprime majoritairement dans les cellules gliales de Müller. Son absence a été associée à une augmentation de la perméabilité vasculaire liée à la délocalisation et à la diminution de l’expression des canaux AQP4 et Kir4.1. La souris Dp71-null est donc un excellent modèle d’étude des pathologies rétiniennes présentant une rupture de la BHR. L’ensemble de nos résultats démontrent que chez la souris déficiente en Dp71 ayant une rupture de la BHR, il est possible de restaurer une perméabilité et une homéostasie rétinienne normale grâce à la surexpression de la Dp71 via les virus adéno-associés. Cette étude est à la base du développement de nouvelles stratégies thérapeutiques dans le traitement de pathologies associées à une rupture de la BHR et à un œdème maculaire, comme la RD ou l’OVCR. / Formation and maintenance of the blood-retinal barrier (BRB) is required for proper vision and breaching of this barrier contributes to the pathology in a wide variety of retinal conditions such as diabetic retinopathy (DR) or Central retinal vein occlusion (CRVO). Dystrophin Dp71 being a key membrane cytoskeletal protein, expressed mainly in Müller glial cells, its absence has been related to BRB permeability through delocalization and down-regulation of the AQP4 and Kir4.1 channels. Dp71-null mouse is thus an excellent model to approach the study of retinal pathologies showing blood-retinal barrier permeability. Our results collectively demonstrated that in Dp71 deficient mouse with compromised barriers, normal BRB permeability and retinal homeostasis can be restored through over-expression of Dp71 via adeno-associated virus. This study is the basis for development of new therapeutic strategies in dealing with diseases with BRB breakdown and macular edema such as DR or CRVO.