Structural remodeling of synapses and circuits is essential to experience-dependent plasticity, as occurs during the consolidation of learned experiences into long-term memory. Immune dysfunction has been implicated in numerous cognitive disorders, including schizophrenia and neurodegenerative diseases, leading to increasing interest in the function of brain-resident macrophages known as microglia, which are the dominant immune cell in the brain parenchyma. We previously published that the IL-1 family cytokine Interleukin-33, which is made by astrocytes during development, signals to its obligate receptor IL1RL1 expressed on microglia to promote microglial activation and phagocytic function. In preliminary data that forms the basis for this proposal, we identify a novel population of IL-33 expressing neurons in two adult brain regions: hippocampus and frontal cortex. In detailed structural analyses in the hippocampus, we find that neuron-specific deletion of IL-33 or microglial- specific deletion of IL-33 R leads to fewer dendritic spines, diminished markers of spine plasticity known as spine head filopodia, and impaired neurogenesis. Furthermore, loss of this signaling pathway leads to deficits in contextual fear conditioning: mice are able to normally learn to recognize a fear context but have a progressive decrease in their ability to discriminate the fear context from a neutral context emerging at 15-30 days post training. Mechanistically, we find that extracellular matrix proteins (the chondroitin sulfate proteoglycans brevican and aggrecan) accumulate in the hippocampus of IL-33 deficient animals. We find that microglia engulf aggrecan, and that loss of IL-33 signaling diminishes this engulfment. We also developed a neuronal gain of function construct that constitutively secretes IL-33. We find this is sufficient to increase hippocampal spine numbers, microglial ECM engulfment, and to clear ECM around dendritic spines. Based on these preliminary data, this proposal will test the central hypothesis that neuron-derived IL-33 drives microglial remodeling of ECM to promote circuit plasticity in support of memory consolidation.
Aim One will explore the molecular regulation of IL-33 release from neurons and its activity dependence, and test two candidate proteases mediating microglial remodeling in response to IL-33.
Aim Two will test the impact of this neuron-microglia signaling on the ECM composition of the frontal cortex with a focus on perineuronal nets and determine its impact on connectivity of the cortical microcircuit.
Aim 3 will use calcium imaging in a contextual fear conditioning task to test how neuronal activity patterns shift during the transition from recent to remote memories, addressing key questions regarding the structural changes that underlie memory consolidation. Together, these studies will systematically dissect the role of a novel cellular circuit regulating plasticity in the healthy brain. The outcome of this work has implications for understanding cognitive dysfunction in numerous diseases linked to microglia and the immune system , including schizophrenia and neurodegenerative conditions such as Alzheimer's Disease.

Public Health Relevance

This study will determine how the immune cells of the brain, known as microglia, change the synaptic connections between nerve cells in the brain. We will test the hypothesis that microglia engulf and remodel a lattice-like structure between cells known as the extracellular matrix. This novel mechanism could help explain how immune signals can impact the formation of long-term memories.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Tonelli, Leonardo H
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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