Astrocyte Extracellular Matrix Modulates Neuronal Dendritic Development

Major developmental events occurring in the hippocampus during the third trimester of human gestation and neonatally in altricial rodents include rapid and synchronized dendritic arborization and astrocyte proliferation and maturation. We tested the hypothesis that signals sent by developing astrocytes to developing neurons modulate dendritic development in vivo. First, we altered neuronal development by exposing neonatal (third trimester-equivalent) mice to ethanol, which increased dendritic arborization in hippocampal pyramidal neurons. We next assessed concurrent changes in the mouse astrocyte translatome by translating ribosomal affinity purification (TRAP)-seq. We followed up on ethanol-inhibition of astrocyte Chpf2 and Chsy1 gene translation because these genes encode biosynthetic enzymes of chondroitin sulfate glycosaminoglycan (CS-GAG) chains (extracellular matrix components that inhibit neuronal development and plasticity) and have not been explored before for their roles in dendritic arborization. We report that Chpf2 and Chsy1 are enriched in astrocytes, and their translation is inhibited by ethanol, which also reduces the levels of CS-GAGs measured by Liquid Chromatography/Mass Spectrometry. Finally, astrocyte-conditioned medium derived from Chfp2-silenced astrocytes increased neurite length and branching of hippocampal neurons in vitro, mechanistically linking changes in CS-GAG biosynthetic enzymes in astrocytes to altered neuronal development. These results demonstrate that CS-GAG biosynthetic enzymes in astrocytes regulate dendritic arborization in developing neurons and are involved in ethanol-induced altered neuronal development.