Gonzalez Laurine, Bezzi Paola
Department of Fundamental Neurosciences (DNF), University of Lausanne (UNIL), Lausanne, Switzerland.
Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
J Neurochem. 2025 May;169(5):e70092. doi: 10.1111/jnc.70092.
Obsessive-compulsive disorder (OCD) has long been conceptualized as a neuron-centric disorder of cortico-striato-thalamo-cortical (CSTC) circuit dysregulation. However, a growing body of evidence is now reframing this narrative, placing astrocytes-once relegated to passive support roles-at the center of OCD pathophysiology. Astrocytes are critical regulators of glutamate and GABA homeostasis, calcium signaling, and synaptic plasticity, all of which are disrupted in OCD. Recent high-resolution molecular and proteomic studies reveal that specific astrocyte subpopulations, including Crym-positive astrocytes, directly shape excitatory/inhibitory balance and control perseverative behaviors by modulating presynaptic inputs from the orbitofrontal cortex. Disruptions in astrocytic neurotransmitter clearance and dopamine metabolism amplify CSTC circuit hyperactivity and reinforce compulsions. This review reframes OCD as a disorder of neuro-glial dysfunctions, proposing that targeting astrocytic signaling, metabolism, and structural plasticity may unlock transformative therapeutic strategies. By integrating human and animal data, we advocate for a glial-centric model of OCD that not only enhances mechanistic understanding but also opens new frontiers for precision treatment.
强迫症（OCD）长期以来一直被视为一种以神经元为中心的皮质-纹状体-丘脑-皮质（CSTC）回路调节障碍的疾病。然而，现在越来越多的证据正在重塑这一观点，将曾经被视为仅起被动支持作用的星形胶质细胞置于强迫症病理生理学的核心位置。星形胶质细胞是谷氨酸和γ-氨基丁酸（GABA）稳态、钙信号传导以及突触可塑性的关键调节因子，而这些在强迫症中均受到破坏。最近的高分辨率分子和蛋白质组学研究表明，特定的星形胶质细胞亚群，包括Crym阳性星形胶质细胞，通过调节来自眶额皮质的突触前输入，直接塑造兴奋性/抑制性平衡并控制强迫行为。星形胶质细胞神经递质清除和多巴胺代谢的紊乱会加剧CSTC回路的过度活跃并强化强迫行为。这篇综述将强迫症重新定义为一种神经-胶质功能障碍性疾病，提出针对星形胶质细胞信号传导、代谢和结构可塑性可能会开启变革性的治疗策略。通过整合人类和动物数据，我们倡导一种以胶质细胞为中心的强迫症模型，这不仅能增强对发病机制的理解，还能为精准治疗开辟新的前沿领域。
