Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders.

Astrocytes negatively impact neuronal development in many models of neurodevelopmental disorders (NDs); however, how they do this, and if mechanisms are shared across disorders, is not known. In this study, we developed a cell culture system to ask how astrocyte protein secretion and gene expression change in three mouse models of genetic NDs (Rett, Fragile X and Down syndromes). ND astrocytes increase release of Igfbp2, a secreted inhibitor of insulin-like growth factor (IGF). IGF rescues neuronal deficits in many NDs, and we found that blocking Igfbp2 partially rescues inhibitory effects of Rett syndrome astrocytes, suggesting that increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified that increased BMP signaling is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X and Rett syndrome astrocytes reverses inhibitory effects on neurite outgrowth. This work provides a resource of astrocyte-secreted proteins in health and ND models and identifies novel targets for intervention in diverse NDs.

The diverse actions of astrocytes during synaptic development.

In the developing brain, cortical circuits are established through a complex process of synaptogenesis, maturation, and synaptic pruning. Astrocytes carry out diverse functions during each of these stages to facilitate the formation of complex networks. Recent work has begun to demonstrate that these heterogeneous roles during excitatory synaptic development are determined by the astrocyte population, brain region, and neuron type. This review will focus on current findings which highlight cell type specific mechanisms of excitatory synaptogenesis, as well as multiple mechanisms engaged by astrocytes to facilitate synaptic maturation and pruning.