Synaptic plasticity is important for information processing, learning, and memory encoding. In particular, homeostatic synaptic plasticity is the ability of neurons to produce compensatory changes at synapses in response to prolonged changes in neuronal activity. This form of synaptic plasticity enables neural circuits to maintain specificity and stability during learning-related processes. Astrocytes, as the most abundant glial cells in the central nervous system, actively regulate synapse formation, functions, and maintenance throughout life, but how they sense changes in neuronal activity or interact with neurons in regulating plasticity at the circuit level is largely unknown. Here, I found that astrocyte-secreted interleukin-33 (IL-33) is a critical regulator of homeostatic synapti...[ Read more ]

Synaptic plasticity is important for information processing, learning, and memory encoding. In particular, homeostatic synaptic plasticity is the ability of neurons to produce compensatory changes at synapses in response to prolonged changes in neuronal activity. This form of synaptic plasticity enables neural circuits to maintain specificity and stability during learning-related processes. Astrocytes, as the most abundant glial cells in the central nervous system, actively regulate synapse formation, functions, and maintenance throughout life, but how they sense changes in neuronal activity or interact with neurons in regulating plasticity at the circuit level is largely unknown. Here, I found that astrocyte-secreted interleukin-33 (IL-33) is a critical regulator of homeostatic synaptic plasticity in the adult hippocampus. The suppression of neuronal activity in the hippocampal cornu ammonis 1 (CA1) region increased the expression and secretion of IL-33 by astrocytes. Moreover, in vivo administration of IL-33 promoted excitatory synapse formation and enhanced synaptic transmission in CA1 hippocampal neurons. The action of IL-33 at synapses is mediated through its neuronal receptor activation and the synaptic recruitment of the scaffold protein PSD-95. Furthermore, IL-33 signaling was found to be required for the neuronal activity blockade-induced increase of hippocampal CA3–CA1 excitatory synapses in vivo, while perturbation of IL-33 signaling results in impaired memory functions. These results reveal a critical role for IL-33 in astrocyte–neuron signaling, and provide insights into how astrocytes maintain homeostasis of the adult hippocampal circuitry.