A growing body of research suggests that glial cells regulate synapse formation, maintenance, and pruning. In the February 1 Science, researchers led by Anna and Ari Molofsky at the University of California, San Francisco, identify a new signal that mediates elimination of synapses. Interleukin-33, released by astrocytes in the developing brain, stimulates microglia to gobble up synapses, they report. Mice lacking the cytokine retained too many synapses and had overactive circuits. Injecting exogenous IL-33, on the other hand, whetted the microglia’s appetite and depleted synapses. “We increasingly appreciate that immune molecules, typically associated with fighting infection, also play beneficial roles in healthy tissues,” Anna Molofsky told Alzforum. It is not yet known if IL-33 plays any role in synapse loss during disease.
- Astrocytes in developing brain release IL-33, which stimulates microglia to eat synapses.
- Mice lacking IL-33 have excess synapses and hyperexcitable circuits.
- In AD mouse models, however, IL-33 lowers amyloid and improves memory.
It is known that microglia and astrocytes prune synapses in the developing brain in response to signals from immune proteins of the complement system (Dec 2013 conference news; Dec 2014 news; Mar 2015 conference news). Because IL-33 mediates repair and remodeling in many tissues, in addition to its role in immune cell maturation and chemotaxis, Molofsky and colleagues wondered if it might contribute to synaptic remodeling as well (Gadani et al., 2015; Pomeshchik et al., 2015; Molofsky et al., 2015).
Joint first authors Ilia Vainchtein and Gregory Chin found that one-month-old IL-33 knockout mice had more electrical activity in their thalamuses than did controls, suggesting overly abundant synapses. Indeed, motor neurons in the spinal cord sported about 50 percent more synapses than did those in controls. Knockouts also had weak sensorimotor reflexes, which are mediated by motor neurons.
How might loss of the cytokine contribute to excess synapses? Neither the cytokine nor its receptor were expressed in neurons of wild-type mice, the authors found. Instead, IL-33 was made only in gray-matter astrocytes, while its receptor, IL1RL1, turned up only on microglia. Therefore, the authors looked for changes in gene expression in these cell types in the IL-33 knockouts. They found almost 500 genes with altered expression in microglia, but no changes in astrocytes.
Turning to microglial activity, the authors detected differences in phagocytosis. Microglia in one-month-old IL-33 knockouts contained only half as many postsynaptic markers as microglia from controls. In contrast, injecting IL-33 into the brain or spinal cord caused microglia to gobble up 50 percent more synapses (see image above). This was determined by both an increase in postsynaptic markers inside microglia and a loss of co-localized pre- and postsynaptic markers on neurons. Mice lacking the IL-33 receptor were protected from this loss. In addition, purified microglia in cultures treated with IL-33 swallowed about twice as many synaptosomes in a day as did control cultures.
The findings indicate that microglia devour synapses, but whether they prune connections from healthy cells or engulf debris from dying neurons remains a mystery, Anna Molofsky noted. She plans to explore the underlying mechanism, as well as how IL-33 interacts with other players in synapse elimination, such as complement. Perhaps IL-33 primes microglia to eat, while complement tags specific synapses for destruction, she suggested.
Another unanswered question is whether IL-33 contributes to neurodegenerative synapse loss, a process triggered by complement (Nov 2015 conference news; May 2016 news). If it does, then having less IL-33 might be beneficial.
However, previous studies in AD mouse models report the opposite. Nancy Ip at the Hong Kong University of Science and Technology, China, found that administering IL-33 to APP/PS1 mice improved memory and synaptic plasticity while lowering soluble Aβ and plaque load (Fu et al., 2016). Conversely, mice lacking this cytokine accumulate DNA damage, develop tauopathy, and lose neurons as they age (Carlock et al., 2017).
In people, too, Jean-Charles Lambert at Institut Pasteur de Lille, INSERM, France, reported that lower IL-33 expression associated with AD, while a protective haplotype that boosts IL-33 expression reduced cerebral amyloid angiopathy (Chapuis et al., 2009).
“As usual in science, the new data complicated the story a bit,” Lambert said. He noted that Molofsky and colleagues examined developing brains, and the effects might be different in aged brains. “It would be informative to see how IL-33 affects pruning as a function of Aβ exposure,” he suggested. Ip believes both her and Molofsky’s findings can be explained by IL-33 stimulating microglial phagocytosis of debris. “It is interesting to speculate that IL-33 clears unwanted materials through the activation of microglia during neural development and in the disease state,” she wrote to Alzforum.—Madolyn Bowman Rogers
- Glial Cells Refine Neural Circuits
- Neurons Cave When Astrocytes Heap on the Complements
- Microglia Rely on Mixed Messages to Select Synapses for Destruction
- Microglia Control Synapse Number in Multiple Disease States
- Microglia Prune Synapses in a Subtype of Frontotemporal Dementia
Research Models Citations
- Gadani SP, Walsh JT, Smirnov I, Zheng J, Kipnis J. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron. 2015 Feb 18;85(4):703-9. Epub 2015 Feb 5 PubMed.
- Pomeshchik Y, Kidin I, Korhonen P, Savchenko E, Jaronen M, Lehtonen S, Wojciechowski S, Kanninen K, Koistinaho J, Malm T. Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury. Brain Behav Immun. 2015 Feb;44:68-81. Epub 2014 Aug 18 PubMed.
- Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. Immunity. 2015 Jun 16;42(6):1005-19. PubMed.
- Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, Ip NY. IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline. Proc Natl Acad Sci U S A. 2016 May 10;113(19):E2705-13. Epub 2016 Apr 18 PubMed.
- Carlock C, Wu J, Shim J, Moreno-Gonzalez I, Pitcher MR, Hicks J, Suzuki A, Iwata J, Quevedo J, Lou Y. Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice. Transl Psychiatry. 2017 Jul 4;7(7):e1164. PubMed.
- Chapuis J, Hot D, Hansmannel F, Kerdraon O, Ferreira S, Hubans C, Maurage CA, Huot L, Bensemain F, Laumet G, Ayral AM, Fievet N, Hauw JJ, Dekosky ST, Lemoine Y, Iwatsubo T, Wavrant-DeVrièze F, Dartigues JF, Tzourio C, Buée L, Pasquier F, Berr C, Mann D, Lendon C, Alpérovitch A, Kamboh MI, Amouyel P, Lambert JC. Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease. Mol Psychiatry. 2009 Nov;14(11):1004-16. PubMed.
- Curbing Innate Immunity Boosts Synapses, Cognition
- Beyond Neighborhood Watch—Microglia Nurture Synapses
- Paper Alert: Microglia Mediate Synaptic Loss in Early Alzheimer’s Disease
- ApoE Variants Modulate Astrocyte Appetite for Synapses
- Microglia Give Astrocytes License to Kill
- Sans Complement: Amyloid Grows, Synapses and Memory Stay
- Vainchtein ID, Chin G, Cho FS, Kelley KW, Miller JG, Chien EC, Liddelow SA, Nguyen PT, Nakao-Inoue H, Dorman LC, Akil O, Joshita S, Barres BA, Paz JT, Molofsky AB, Molofsky AV. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science. 2018 Feb 1; PubMed.