Inflammasome signaling in astrocytes modulates hippocampal plasticity

Emerging evidence indicates that a baseline level of controlled innate immune signaling is required to support proper brain function. However, little is known about the function of most innate immune pathways in homeostatic neurobiology. Here, we report a role for astrocyte-dependent inflammasome signaling in regulating hippocampal plasticity. Inflammasomes are multiprotein complexes that promote caspase-1-mediated interleukin (IL)-1 and IL-18 production in response to pathogens and tissue damage. We observed that inflammasome complex formation was regularly detected under homeostasis in hippocampal astrocytes and that its assembly is dynamically regulated in response to learning and regional activity. Conditional ablation of caspase-1 in astrocytes limited hyperexcitability in an acute seizure model and impacted hippocampal plasticity via modulation of synaptic protein density, neuronal activity, and perineuronal net coverage. Caspase-1 and IL-18 regulated hippocampal IL-33 production and related plasticity. These findings reveal a homeostatic function for astrocyte inflammasome activity in regulating hippocampal physiology in health and disease.