Synapse Formation, Neurons, Glial Support Cells

 

Science  16 Mar 2018: Vol. 359, Issue 6381, pp. 1269-1273

Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development

Ilia D. Vainchtein, et.al.

Department of Psychiatry/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.

Department of Otolaryngology, University of California, San Francisco, San Francisco, CA, USA.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA.

Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.

Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.

Department of Neurobiology, Stanford University, Palo Alto, CA, USA.

Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.

Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan.

[paraphrase]

Neuronal synapse formation and remodeling are essential to central nervous system (CNS) development and are dysfunctional in neurodevelopmental diseases. Innate immune signals    regulate tissue remodeling in the periphery, but how this affects CNS synapses is largely unknown. Here, we show that the interleukin-1 family cytokine     interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus. We find that IL-33 signals primarily to microglia under physiologic conditions, that it promotes microglial synapse engulfment, and that it can drive microglial-dependent synapse depletion in vivo. These data reveal a cytokine-mediated mechanism required to maintain synapse homeostasis during CNS development.

Neuronal synapse formation depends on a complex interplay between neurons and their glial support cells. Astrocytes provide structural, metabolic, and trophic support for neurons. Gray-matter astrocytes are in intimate contact with neuronal synapses and are poised to sense local neuronal cues. In contrast, microglia are the primary immune cells of the central nervous system (CNS) parenchyma. Microglia regulate multiple phases of developmental circuit refinement, both inducing synapse formation and promoting synapse engulfment, in part via complement, an effector arm of the innate immune system. Excess complement activity has been implicated in schizophrenia, a neurodevelopmental disorder that includes cortical gray matter thinning and synapse loss, suggesting that microglial synapse engulfment may have broad implications for neuropsychiatric disease.

Despite the emerging roles of astrocytes and microglia in neuronal synapse formation and remodeling, how they coordinate synaptic homeostasis in vivo remains obscure. Interleukin-33 (IL-33) is an IL-1 family member with well-described roles as a cellular alarmin released from nuclear stores after tissue damage, including in spinal cord injury, stroke, and Alzheimer’s disease. Whereas many cytokines are primarily defined by their roles in inflammation and disease (e.g., IL-1, tumor necrosis factor–α, or IL-6), IL-33 also promotes homeostatic tissue development and remodeling. The CNS undergoes extensive synapse remodeling during postnatal brain development, but a role for IL-33 or other stromal-derived cytokines is unknown. Here, we report that IL-33 is produced postnatally by synapse-associated astrocytes, is required for synaptic development in the thalamus and spinal cord, and signals to microglia to promote increased synaptic engulfment. These findings reveal a physiologic requirement for cytokine-mediated immune signaling in brain development.

Our data reveal a mechanism of astrocyte-microglial communication that is required for synapse homeostasis during CNS development. We propose that astrocyte-derived IL-33 serves as a rheostat, helping to tune microglial synapse engulfment during neural circuit maturation and remodeling. Key unanswered questions include the nature of the cues that induce astrocyte Il33 expression, the mechanism of IL-33 release, and the signals downstream of IL-33 that promote microglial function. These data also raise the broader question of how this process affects neural circuit function. Synapses are the most tightly regulated variable in the developing CNS and are a primary locus of dysfunction in neurodevelopmental diseases. Il33 is one of five genes that molecularly distinguish astrocytes from neural progenitors in the developing human forebrain, suggesting possibly conserved roles in the human CNS. Defining whether signals like IL-33 are permissive or instructive, promiscuous or synapse specific, is a first step toward understanding how neural circuits remodel during development and under stress.

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