If a nerve cannot talk to another nerve, problems may occur. Loss of myelin will slow nerve transmission but if there is no synapse (the point where one nerve contacts another nerve) there is no nerve signal transmission. In this study they look at the visual system and they find that synapses are lost, even if there is seemingly no demyelination, They showed that microglia are removing the synapses after they are programmed to be eaten by the deposition of a protein called complement. This is because microglia have complement receptors. When they blocked microglial targeting of the synapse. This was associated with less loss of function.
Now the easy thing to say is let’s block this, but it may not all be good news. It is possible that loss of a synapse may protect the nerve from too much excitation that would otherwise cause nerve damage. The other issue is to what extent blocking this pathway could be detrimental. Every day we make new synapses as we make new memories, but each night we have to forget a lot of stuff so we can make new memories for the day. Synapses need to be cleared and microglia are no doubt involved in this. So how we target the unwanted synapse stripping from the everyday synapse removal will be a therapeutic problem
Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease. Werneburg S, Jung J, Kunjamma RB, Ha SK, Luciano NJ, Willis CM, Gao G, Biscola NP, Havton LA, Crocker SJ, Popko B, Reich DS, Schafer DP. Immunity. 2019 Dec 23. pii: S1074-7613(19)30523-0.
Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on myelin and axon loss in MS, less is known about mechanisms underlying synaptic changes. Using post-mortem human MS tissue, a preclinical non-human primate model of MS, and two rodent models of demyelinating disease, we investigated synapse changes in the visual system. Similar to other neurodegenerative diseases, microglial synaptic engulfment and profound synapse loss were observed. In mice, synapse loss occurred independently of local demyelination and neuronal degeneration but coincided with gliosis and increased complement component C3, but not C1q, at synapses. Viral overexpression of the complement inhibitor Crry at C3-bound synapses decreased microglial engulfment of synapses and protected visual function. These results indicate that microglia eliminate synapses through the alternative complement cascade in demyelinating disease and identify a strategy to prevent synapse loss that may be broadly applicable to other neurodegenerative diseases.