Abstract
Resident microglia are the main immune cells in the retina and play a key role in the pathogenesis of retinitis pigmentosa (RP). Many previous studies on the roles of microglia mainly focused on the neurotoxicity or neuroprotection of photoreceptors, while their contributions to synaptic remodeling of neuronal circuits in the retina of early RP remained unclarified. In the present study, we used Royal College of Surgeons (RCS) rats, a classic RP model characterized by progressive microglia activation and synapse loss, to investigate the constitutive effects of microglia on the synaptic lesions and ectopic neuritogenesis. Rod degeneration resulted in synapse disruption and loss in the outer plexiform layer (OPL) at the early stage of RP. Coincidentally, the resident microglia in the OPL increased phagocytosis and mainly engaged in phagocytic engulfment of postsynaptic mGluR6 of rod bipolar cells (RBCs). Complement pathway might be involved in clearance of postsynaptic elements of RBCs by microglia. We pharmacologically deleted microglia using a CSF1 receptor (CSF1R) inhibitor to confirm this finding, and found that it caused the accumulation of postsynaptic mGluR6 levels and increased the number and length of ectopic dendrites in the RBCs. Interestingly, the numbers of presynaptic sites expressing CtBP2 and colocalized puncta in the OPL of RCS rats were not affected by microglia elimination. However, sustained microglial depletion led to progressive functional deterioration in the retinal responses to light in RCS rats. Based on our results, microglia mediated the remodeling of RBCs by phagocytosing postsynaptic materials and inhibiting ectopic neuritogenesis, contributing to delay the deterioration of vision at the early stage of RP.
Highlights
Retinitis pigmentosa (RP) represents a group of retinal diseases typically attributed to hereditary factors that are caused by mutations predominantly expressed in photoreceptors or retinal pigment epithelial (RPE) cells, that contribute to rod degeneration followed by gradual death of cones [1]
The synapses between rods and rod bipolar cells (RBCs) consisted of horseshoe-like, CtBP2-positive presynaptic ribbons, accompanied by a single, dot-like, mGluR6-positive postsynaptic structure; these pairs were distributed in the outermost part of the outer plexiform layer (OPL) (Figure 1A and Supplementary Figure 1B)
The synapse between a cone and a cone bipolar cell consisted of 3-4 CtBP2-labeled presynaptic structures and a mGluR6labeled disk-like postsynaptic structure; these pairs were mainly distributed within the innermost part of the OPL (Figure 2A and Supplementary Figures 1F,G)
Summary
Retinitis pigmentosa (RP) represents a group of retinal diseases typically attributed to hereditary factors that are caused by mutations predominantly expressed in photoreceptors or retinal pigment epithelial (RPE) cells, that contribute to rod degeneration followed by gradual death of cones [1]. At the early stage of RP, the retina is characterized by Microglia and Early Vision Maintenance of RP the down regulation and mislocalization of proteins of the pre- and postsynaptic machinery in the outer plexiform layer (OPL) in mouse [2,3,4] and rat [5] RP models. In the rd mouse model of RP, which is induced by a mutation in the rod photoreceptor-specific Pde6b gene, photoreceptor stress is accompanied by the loss of axon terminals in photoreceptors and dendritic retraction in bipolar and horizontal cells [6, 7]. In Royal College of Surgeons (RCS) rats, a RP model that characterized with defective phagocytosis of photoreceptor outer segments by RPE cells [9], the presynaptic and postsynaptic structures in the OPL are impaired as early as postnatal day 21 (P21) and completely lost at P90 [5]. The mechanisms of synapse loss in RP are not completely understood
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