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Microglia target synaptic sites early during excitatory circuit disassembly in neurodegeneration
Alfred Yu1, Camille Fang1, Li Xuan Tan1,2
1Department of Ophthalmology, UCSF School of Medicine, San Francisco, CA, USA.
Abstract:
During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, understanding the role of microglia-mediated synaptic pruning in circuit remodeling and dysfunction is important for developing therapies aimed at modulating microglial function. Here, we analyzed microglia-mediated synapse disassembly of degenerating postsynaptic neurons in the inner retina. After inducing transient intraocular pressure elevation to injure retinal ganglion cells, microglia increase in number, shift to hyper-ramified morphology, and exhibit greater process movement. Furthermore, due to the greater number of microglia, there is increased colocalization of microglia with synaptic components throughout the inner plexiform layer and with excitatory synaptic sites along individual ganglion cell dendrites. Microglia depletion partially protects ganglion cell function, suggesting that microglia activation may be neurotoxic in early neurodegeneration. Our results demonstrate the important role of microglia in synapse disassembly in degenerating circuits, highlighting that microgliosis is the primary mechanism for increased synapse colocalization early after neuronal injury.
Insights
Microglia play a key role in synapse loss in degenerating retinal circuits. Their activation, termed microgliosis, may be neurotoxic in early neurodegeneration, impacting ganglion cell function.
Area of Science:
- Neuroscience
- Immunology
- Ophthalmology
Background:
- Microglia are immune cells in the brain crucial for synaptic pruning during development.
- Understanding microglial roles in neurodegeneration is vital for therapeutic development.
- Synaptic dysfunction is a hallmark of neurodegenerative diseases, including those affecting the retina.
Purpose of the Study:
- To investigate microglia-mediated synapse disassembly in degenerating retinal ganglion cells.
- To analyze the impact of microglial activation on synaptic components after neuronal injury.
Main Methods:
- Induction of transient intraocular pressure elevation to model retinal injury.
- Analysis of microglial number, morphology, and process movement.
- Quantification of microglia-synaptic component colocalization in the inner retina.
- Assessment of retinal ganglion cell function following microglia depletion.
Main Results:
- Induced retinal injury led to increased microglial numbers, hyper-ramified morphology, and enhanced process activity.
- Increased colocalization of microglia with synaptic elements was observed throughout the inner plexiform layer and on ganglion cell dendrites.
- Microglia depletion partially preserved ganglion cell function, suggesting a neurotoxic role for activated microglia.
Conclusions:
- Microgliosis is the primary mechanism driving increased synapse colocalization early after retinal neuronal injury.
- Microglia-mediated synapse disassembly is a significant factor in degenerating neuronal circuits.
- Activated microglia may exert neurotoxic effects in the early stages of neurodegeneration.
