| Abstract: | Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.Synaptic plasticity, the ability of neurons to alter the structure and strength of synapses, is important for the refinement of neuronal circuits in response to sensory experience during development (1) as well as learning and memory formation in adults (2, 3). To maintain the stability of neuronal network activity, the synaptic strength of neurons is modified through a negative-feedback mechanism termed homeostatic synaptic plasticity (4–6). Specifically, inhibiting neuronal activity in cultured neuronal cells or hippocampal slices by pharmacological administration of the sodium channel blocker tetrodotoxin (TTX) increases the strength of excitatory synapses to rebalance network activity (5–7).The hippocampus, which comprises the cornu ammonis 1 (CA1), CA2, CA3, and dentate gyrus subregions, is important for memory storage and retrieval. In particular, the CA1 subregion constitutes the primary output of the hippocampus, which is thought to be essential for most hippocampus-dependent memories (8, 9). Moreover, experience-driven synaptic changes in the CA1 microcircuitry impact how information is integrated (10, 11). Accordingly, the induction and expression of synaptic plasticity at hippocampal CA1 excitatory synapses are critically dependent on the structural remodeling and composition of synapses as well as functional modifications of pre- and postsynaptic proteins and neurotransmitter receptors (4–6, 12). As such, structural plasticity is a major regulatory mechanism of homeostatic synaptic plasticity in the hippocampal CA1 region. While most excitatory synapses are located at dendritic spines, morphological changes of dendritic spines likely participate in compensatory adaptations of hippocampal network activity and are therefore involved in learning, memory formation (13), and memory extinction (14).The efficacy of synaptic transmission and the wiring of neuronal circuitry are regulated not only by bidirectional communication between pre- and postsynaptic neurons, but also through the interactions between neurons and their associated glial cells (15–17). Astrocytes, as the most abundant type of glia in the central nervous system, actively regulate synapse formation, function, and maintenance during development and in the adult brain (18–20). However, the molecular basis of astrocyte–neuron communication in synaptic plasticity is largely unknown. Nevertheless, one of the mechanisms by which astrocytes regulate synapses is by secreting factors (21–25); the most well-characterized one is TNFα. Notably, pharmacologically induced deprivation of neuronal activity increases TNFα release from astrocytes, which modulates homeostatic plasticity in both excitatory and inhibitory neurons through regulation of neuronal glutamate and GABA receptor trafficking (24, 26). Further in vivo studies on germline knockout mice support the roles of astrocyte-secreted TNFα in homeostatic adaptations of cortical circuitry during sensory deprivation (27, 28). Another cytokine interleukin-33 (IL-33) is secreted by astrocytes to regulate synapse development in spinal cord and thalamus (29). Nevertheless, it remains largely unknown how astrocytes respond to changes in neuronal activity to regulate homeostatic synaptic plasticity in the hippocampus as well as learning and memory formation.In this study, we identified IL-33 as an astrocyte-secreted factor which mediates homeostatic synaptic plasticity in the CA1 subregion of adult hippocampus. Pharmacological blockade of neuronal activity or in vivo optogenetic inhibition of CA1 pyramidal neurons stimulates a local increase in the expression and release of IL-33 from the astrocytes. In turn, this astrocyte-secreted IL-33 and its ST2/IL-1RAcP receptor complex mediate the increase of excitatory synapses and neurotransmission in homeostatic synaptic plasticity. Two-photon imaging of CA1 pyramidal neurons in vivo reveals that IL-33 promotes dendritic spine formation through the synaptic recruitment of postsynaptic scaffolding protein PSD-95. Importantly, conditional knockout of IL-33 in astrocytes decreases excitatory synapses in the CA1 subregion, and inhibition of IL-33/ST2 signaling in adult mice abolishes the homeostatic synaptic plasticity in CA1 pyramidal neurons, resulting in impaired spatial memory formation. Hence, our findings collectively show that astrocyte-secreted IL-33 plays an important role in homeostatic synaptic plasticity in the adult hippocampus and spatial memory formation. |
