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., 2018; Frischknecht 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
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- Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, Taloma SE, Barron JJ, Molofsky AB, Kheirbek MA, Molofsky AV. Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity. Cell. 2020 Jul 23;182(2):388-403.e15. Epub 2020 Jul 1 PubMed.