Suppression of astrocyte BMP signaling improves molecular signatures and functional deficits in a fragile X syndrome mouse model.

Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with molecular, neuroanatomical, and behavioral changes. In FXS, astrocytes express dysregulated gene and protein networks, therefore identifying upstream pathways mediating astrocyte changes may provide a point of intervention. We focus on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, finding that this lessens audiogenic seizure severity in male FXS mice. We performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted and membrane proteins in FXS astrocytes, with these alterations mitigated when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses in the FXS auditory cortex. Our findings show that astrocytes contribute to some FXS mouse molecular and functional phenotypes, and targeting astrocyte BMP signaling improves some FXS symptoms.