Microglia target synaptic sites early during excitatory circuit disassembly in neurodegeneration

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. HighlightsEarly after transient intraocular pressure elevation: O_LIMicroglia increase in number, complexity, and process movement C_LIO_LIMicroglia-synaptic contacts increase in the inner plexiform layer C_LIO_LIMicroglia-synaptic contacts increase on retinal ganglion cell dendrites C_LIO_LIMicroglia depletion partially restores ganglion cell function C_LI