Microglia Mediate Synaptic Material Clearance at the Early Stage of Rats With Retinitis Pigmentosa

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.

Microglia Inhibition Delays Retinal Degeneration Due to MerTK Phagocytosis Receptor Deficiency

“…Indeed, numerous engulfment receptors relevant to efferocytosis are known (62). Moreover, increased staining of complement factor C1q has been reported in RCS retina in the OPL where microglia may phagocytose synaptic components (63). The same study found that elimination of retinal microglia by systemic treatment with a CSF1 receptor inhibitor had no effect on photoreceptor light responses (and worsened inner retinal responses), although drug administration via dietary supplementation only started at P15 and may not have been effective immediately in pre-weaning rats.…”

Aging with Toxoplasma gondii results in pathogen clearance, resolution of inflammation, and minimal consequences to learning and memory

“…If these neurons were injected with parasite protein (either with or without subsequent invasion) during early CNS infection, their survival would suggest that not all T. gondii-injected neurons are cleared from the CNS. The lack of clearance over the long-term would imply that these neurons are functional, as non-functional neurons are normally cleared by microglia 65,66 . Alternatively, if parasitic cysts continually rupture, individual parasites may interact with and invade new neurons continually throughout the host's lifetime.…”

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

“…Microglial activation is an important hallmark of neuroin ammatory diseases including AMD [14,21,22], as resident immunizing cells in retina, microglia sustain microenvironmental equilibrium and its dysfunction initiates a series of retinal degenerative performance [17,[23][24][25][26]. Therefore, considered that there was no well-established AMD animal models to mimic both the etiological and morphological properties of AMD [27,28], we focused on microglial activation by subretinal injection of Aβ 1-42 in mice and studied its indirect effect on photoreceptors by releasing the in ammatory cytokines.…”