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Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer
- Source :
- The Journal of clinical investigation, vol 125, iss 7
- Publication Year :
- 2015
-
Abstract
- Strategies aimed at invoking synaptic plasticity have therapeutic potential for several neurological conditions. The human retinal synaptic disease X-linked retinoschisis (XLRS) is characterized by impaired visual signal transmission through the retina and progressive visual acuity loss, and mice lacking retinoschisin (RS1) recapitulate human disease. Here, we demonstrate that restoration of RS1 via retina-specific delivery of adeno-associated virus type 8-RS1 (AAV8-RS1) vector rescues molecular pathology at the photoreceptor-depolarizing bipolar cell (photoreceptor-DBC) synapse and restores function in adult Rs1-KO animals. Initial development of the photoreceptor-DBC synapse was normal in the Rs1-KO retina; however, the metabotropic glutamate receptor 6/transient receptor potential melastatin subfamily M member 1-signaling (mGluR6/TRPM1-signaling) cascade was not properly maintained. Specifically, the TRPM1 channel and G proteins Gαo, Gβ5, and RGS11 were progressively lost from postsynaptic DBC dendritic tips, whereas the mGluR6 receptor and RGS7 maintained proper synaptic position. This postsynaptic disruption differed from other murine night-blindness models with an electronegative electroretinogram response, which is also characteristic of murine and human XLRS disease. Upon AAV8-RS1 gene transfer to the retina of adult XLRS mice, TRPM1 and the signaling molecules returned to their proper dendritic tip location, and the DBC resting membrane potential was restored. These findings provide insight into the molecular plasticity of a critical synapse in the visual system and demonstrate potential therapeutic avenues for some diseases involving synaptic pathology.
- Subjects :
- Male
Retinoschisis
Knockout
Genetic Vectors
Immunology
TRPM Cation Channels
Inbred C57BL
Eye
Medical and Health Sciences
Mice
Receptors
Metabotropic Glutamate
Electroretinography
Genetics
Animals
Humans
2.1 Biological and endogenous factors
Photoreceptor Cells
Calcium Signaling
Aetiology
Eye Proteins
Eye Disease and Disorders of Vision
Neuronal Plasticity
Animal
Vertebrate
Neurosciences
Genetic Therapy
Dependovirus
Synapses
Disease Models
Neurological
Cell Adhesion Molecules
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation, vol 125, iss 7
- Accession number :
- edsair.dedup.wf.001..5e900fb806829e7d13344e9649d1e5fc