Astrocyte Extracellular Matrix Modulate Neuronal Dendritic Development

Joel G Hashimoto, Nicholas Margolies,Xiaolu Zhang, Joshua Karpf,Yuefan Song,Brett A Davis,Fuming Zhang,Robert J Linhardt,Lucia Carbone,Marina Guizzetti

bioRxiv the preprint server for biology（2024）

Department of Behavioral Neuroscience | Rensselaer Polytechnic Institute | Oregon Health & Science University | Oregon health & science university

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Abstract

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. We altered neuronal development by neonatal (third trimester-equivalent) ethanol exposure in mice; this treatment 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 for 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 branching of hippocampal neurons in vitro. These results demonstrate that CS-GAG biosynthetic enzymes in astrocytes regulates dendritic arborization in developing neurons.

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【要点】：本文发现星形胶质细胞外基质通过调节透明质酸糖胺聚糖链的生物合成酶Chpf2和Chsy1，影响神经元树突的发展。

【方法】：通过向小鼠体内暴露乙醇以改变神经元发育，并使用翻译核糖体亲和纯化（TRAP）-seq技术分析星形胶质细胞翻译组的变化。

【实验】：实验在新生小鼠（相当于人类妊娠第三季度）中进行，通过液体色谱/质谱技术测量了乙醇处理后星形胶质细胞Chpf2和Chsy1基因的翻译抑制及CS-GAGs水平的降低，并在体外实验中使用来自Chpf2沉默星形胶质细胞的条件培养基，观察到海马神经元树突分支的增加。