Astrocytes and neurons extensively interact in the brain. Identifying astrocyte and neuron proteomes is essential for elucidating the protein networks that dictate their respective contributions to physiology and disease. Here we used cell-specific and subcompartment-specific proximity-dependent biotinylation¹ to study the proteomes of striatal astrocytes and neurons in vivo. We evaluated cytosolic and plasma membrane compartments for astrocytes and neurons to discover how these cells differ at the protein level in their signalling machinery. We also assessed subcellular compartments of astrocytes, including end feet and fine processes, to reveal their subproteomes and the molecular basis of essential astrocyte signalling and homeostatic functions. Notably, SAPAP3 (encoded by Dlgap3), which is associated with obsessive–compulsive disorder (OCD) and repetitive behaviours^{2,3,4,5,6,7,8}, was detected at high levels in striatal astrocytes and was enriched within specific astrocyte subcompartments where it regulated actin cytoskeleton organization. Furthermore, genetic rescue experiments combined with behavioural analyses and molecular assessments in a mouse model of OCD⁴ lacking SAPAP3 revealed distinct contributions of astrocytic and neuronal SAPAP3 to repetitive and anxiety-related OCD-like phenotypes. Our data define how astrocytes and neurons differ at the protein level and in their major signalling pathways. Moreover, they reveal how astrocyte subproteomes vary between physiological subcompartments and how both astrocyte and neuronal SAPAP3 mechanisms contribute to OCD phenotypes in mice. Our data indicate that therapeutic strategies that target both astrocytes and neurons may be useful to explore in OCD and potentially other brain disorders.

星形胶质细胞和神经元在大脑中广泛相互作用。识别星形胶质细胞和神经元蛋白质组对于阐明决定它们各自对生理学和疾病的贡献的蛋白质网络至关重要。在这里，我们使用细胞特异性和亚区室特异性邻近依赖性生物素化¹来研究体内纹状体星形胶质细胞和神经元的蛋白质组。我们评估了星形胶质细胞和神经元的细胞质和质膜区室，以发现这些细胞在其信号机制的蛋白质水平上有何不同。我们还评估了星形胶质细胞的亚细胞区室，包括末端脚和精细过程，以揭示其亚蛋白质组以及重要星形胶质细胞信号传导和稳态功能的分子基础。值得注意的是，SAPAP3（由Dlgap3编码）与强迫症 (OCD) 和重复行为相关^{2,3,4,5,6,7,8} ，在纹状体星形胶质细胞中检测到高水平，并且在特定的区域内富集。星形胶质细胞亚区室，调节肌动蛋白细胞骨架组织。此外，在缺乏 SAPAP3 的 OCD ⁴小鼠模型中进行的基因拯救实验与行为分析和分子评估相结合，揭示了星形细胞和神经元 SAPAP3 对重复和焦虑相关的 OCD 样表型的独特贡献。我们的数据定义了星形胶质细胞和神经元在蛋白质水平及其主要信号传导通路上的差异。此外，他们还揭示了星形胶质细胞亚蛋白质组在生理亚区之间如何变化，以及星形胶质细胞和神经元 SAPAP3 机制如何影响小鼠的强迫症表型。 我们的数据表明，针对星形胶质细胞和神经元的治疗策略可能有助于探索强迫症和其他潜在的脑部疾病。