Synaptic connections in the brain are highly plastic, continuously forming and disconnecting to help enshrine new experiences into memories throughout life. A study published in Cell on July 1 describes a mechanism involved. Researchers led by Anna Molofsky at the University of California, San Francisco, report that in response to new experiences, neurons in the mouse hippocampus release the cytokine IL-33, which then triggers nearby microglia to prune synapses and nibble at their surrounding extracellular matrix. This paves the way for the formation of new, synapse-studded dendritic spines, and is essential for consolidating precise memories in mice. The researchers also found that levels of the cytokine flag with age in the mouse brain, and that boosting IL-33 function preserves synaptic plasticity and memory.

• Hippocampal neurons secrete IL-33 in response to experiences.
• IL-33 triggers microglial phagocytosis of extracellular matrix
• Without neuronal IL-33, dendritic spines are lost, memory fades

Glial cells play a pivotal role in the wiring of the brain’s circuitry, a feat that involves both the formation of new synaptic connections as well as intensive pruning of weak or inactive synapses. Previously, the researchers reported that during development, astrocytes secrete IL-33, which stimulates microglia to prune synapses (Feb 2018 news). They found that this astrocytic source of IL-33 was critical for the formation of healthy synaptic circuitry. The current study extends the cytokine’s role to also promoting synaptic plasticity in the adult brain, an ongoing process that is essential for learning and memory throughout life.

Weeding the Synaptic Garden. In response to experience, hippocampal neurons secrete IL-33, which triggers microglia to engulf extracellular matrix surrounding synapses. This paves the way for fresh synaptic connections and facilitates memory.

To investigate the role of IL-33 in learning and memory, first author Phi Nguyen and colleagues started by searching for the source of the cytokine in the hippocampus. There, they found that neurons—not astrocytes—expressed IL-33. Expression of IL-33 by these hippocampal neurons soared when mice were placed in an enriched environment (EE) with access to toys and a running wheel—a situation known as spark remodeling of synaptic circuitry.

The researchers knocked out IL-33 from neurons, or its receptor from microglia; this reduced the number of dendritic spines on hippocampal neurons, and also dampened neurogenesis in the dentate gyrus. Hobbling this neuron-to-microglia communication also blurred fear memories in the mice.

Levels of the cytokine plummeted naturally with age, in step with memory loss. Expressing an IL-33 mutant with enhanced function in the mouse brain counteracted this age-related dip in synaptic plasticity and memory.

Ultimately, the researchers found that IL-33 promoted microglial phagocytosis of the extracellular matrix (ECM) near neuronal synapses. Previous studies have reported that ECM proteins can restrict synaptic plasticity and spine remodeling (Bolós et al., 2018Frischknecht et al., 2009; and Oray et al., 2004). The researchers found that without IL-33 secreted by neurons, microglia did not engulf the ECM, allowing it to build up around synapses.

Overall, the paper suggest that neurons use IL-33 to motivate microglia to clean up around synapses, which promotes the sprouting of fresh spines and, in this way, supports the consolidation of memory.—Jessica Shugart

Comments

  1. As an alarmin, interleukin-33 (IL-33) is expressed and secreted by neural cells, including astrocytes and oligodendrocytes, to maintain tissue homeostasis (Liew et al., 2016). In this study, Nguyen et al reports an unexpected role of neuronal IL-33 in synapse remodelling in the hippocampus and memory consolidation. They show that experience-dependent increase of IL-33 from a neuronal subpopulation enhances structural synapse formation, and promotes synaptic plasticity through a microglial-dependent engulfment of extracellular matrix.

    The authors demonstrate that IL-33 is expressed in a neuronal subpopulation in the dentate gyrus and that its secretion is regulated by experience. They further show that the secreted IL-33 regulates experience-dependent synaptic remodeling by modulating microglial clearance of the extracellular matrix. Whereas the IL-33-dependent neuron/microglial signaling is required for remote memory precision, the IL-33 expression in the hippocampus decreases upon aging and is associated with impaired memory precision. Their work clearly delineates how IL-33 is regulated in a subset of hippocampal neurons by experience and its role in promoting synapse formation through activation of microglial phagocytosis.

    Interestingly, our unpublished observation also shows that IL-33 release in the hippocampal CA1 region is regulated by experience, pointing toward a role of astrocytic IL-33 in CA1 synaptic plasticity. Therefore, it is likely that IL-33 is released from distinct neural cell types to enhance synapse formation in specific neural circuits in response to experience.

    The authors further show that the proportion of IL-33-positive neurons decreases in aged mice and is associated with reduced spine density. While it is unclear why neuronal IL-33 decreases with aging, this data supports the notion that impaired IL-33/ST2 signaling contributes to age-related cognitive decline. Indeed, this idea is in line with previous reports that reduced transcript level of IL-33 in Alzheimer’s disease brain (Chapuis et al., 2009) and increased level of IL-33 decoy receptor sST2 in the serum of patients with mild cognitive impairment (Fu et al., 2016) is associated with Alzheimer’s disease progression. Therefore, it is intriguing to speculate that decreased IL-33/ST2 signaling is the key driver of hippocampal synaptic dysfunction in Alzheimer’s disease. Of note, we have previously demonstrated that replenishing IL-33 can improve the impaired hippocampal synaptic plasticity in an Aβ-deposition transgenic mouse model (Fu et al., 2016). It would be of great interest to investigate whether IL-33 directly regulates hippocampal synaptic remodeling in Alzheimer’s disease.

    Here, the authors have shown that IL-33 is necessary and sufficient for the microglial phagocytosis and clearance of the extracellular matrix. Thus, this finding has further expanded the repertoire of IL-33-induced microglial functions in addition to phagocytosis of Aβ plaques (Fu et al., 2016; Lau et al., 2020), restraining CNS injury (Gadani et al., 2015), and synaptic pruning (Vainchtein et al., 2018).

    Our recent study shows that IL-33 administration induces a microglial subpopulation, termed IL-33-responsive microglia (IL-33RM) (Lau et al., 2020); these microglia are MHC-II+ with enhanced phagocytosis and clearance capacity. Moreover, IL-33 induces the state transition and functional modulation of microglia through regulation of their epigenetic landscape, including chromatin accessibility and PU.1 binding. Hence, it would be of interest to examine whether similar regulatory control of the microglial state transition occurs in hippocampal synaptic plasticity in health and Alzheimer’s disease. Given that PU.1 can interact with various transcription factors in transcriptome regulation (Glass and Natoli, 2016; Heinz et al., 2010), understanding how PU.1 transcription factor complexes control microglial state transition might provide insight into the molecular control of microglial dysfunction in Alzheimer’s disease.

    References:

    . Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease. Mol Psychiatry. 2009 Nov;14(11):1004-16. PubMed.

    . 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.

    . 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.

    . Molecular control of activation and priming in macrophages. Nat Immunol. 2016 Jan;17(1):26-33. PubMed.

    . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010 May 28;38(4):576-89. PubMed.

    . IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer's Disease. Cell Rep. 2020 Apr 21;31(3):107530. PubMed.

    . Interleukin-33 in health and disease. Nat Rev Immunol. 2016 Nov;16(11):676-689. Epub 2016 Sep 19 PubMed.

    . Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science. 2018 Mar 16;359(6381):1269-1273. Epub 2018 Feb 1 PubMed.

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References

News Citations

  1. Astrocytic IL-33 Signals Microglia to Engulf Synapses

Paper Citations

  1. . Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci. 2009 Jul;12(7):897-904. Epub 2009 May 31 PubMed.
  2. . Dendritic spine dynamics are regulated by monocular deprivation and extracellular matrix degradation. Neuron. 2004 Dec 16;44(6):1021-30. PubMed.

Further Reading

Primary Papers

  1. . Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity. Cell. 2020 Jun 26; PubMed.