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Microglia target synaptic sites early during excitatory circuit disassembly in neurodegeneration
Alfred Yu1, Li Xuan Tan1, Aparna Lakkaraju1
1Department of Ophthalmology, UCSF School of Medicine, San Francisco, CA, USA.
Abstract:
During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, 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 the role of microglia in the 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 ameboid 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 restores 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 their recruitment to synaptic sites early after neuronal injury.
Insights
Microglia play a key role in synapse loss in the degenerating retina. Reducing microglia activity partially restored vision, suggesting they may be neurotoxic in early neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
Background:
- Microglia, the immune cells of the central nervous system, are crucial for synaptic pruning during development.
- Their role in synaptic remodeling and dysfunction in neurodegeneration is critical for therapeutic development.
Purpose of the Study:
- To investigate the role of microglia in synapse disassembly in degenerating postsynaptic neurons within the inner retina.
Main Methods:
- Transient intraocular pressure elevation was used to induce injury in retinal ganglion cells.
- Microglial activation, morphology, process movement, and colocalization with synaptic components were analyzed.
- Microglia depletion was performed to assess its impact on ganglion cell function.
Main Results:
- Induced injury led to increased microglial numbers, ameboid morphology, and enhanced process movement.
- Increased microglial presence resulted in greater colocalization with synaptic components and excitatory synaptic sites.
- Partial restoration of ganglion cell function was observed after microglia depletion.
Conclusions:
- Microglia are significantly involved in synapse disassembly in degenerating retinal circuits.
- Microglial activation may exert neurotoxic effects during the early stages of neurodegeneration.
- Targeting microglial function presents a potential therapeutic strategy for retinal neurodegenerative diseases.
