Barcelona Clínic Schizophrenia Unit (BCSU). Institute of Neuroscience, Hospital Clínic of Barcelona, University of Barcelona, Barcelona, Catalonia, Spain.
The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Catalonia, Spain.
Transl Psychiatry. 2021 May 6;11(1):271. doi: 10.1038/s41398-021-01385-9.
Schizophrenia disorder remains an unsolved puzzle. However, the integration of recent findings from genetics, molecular biology, neuroimaging, animal models and translational clinical research offers evidence that the synaptic overpruning hypothesis of schizophrenia needs to be reassessed. During a critical period of neurodevelopment and owing to an imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, a regionally-located glutamate storm might occur, triggering excessive dendritic pruning with the activation of local dendritic apoptosis machinery. The apoptotic loss of dendritic spines would be aggravated by microglia activation through a recently described signaling system from complement abnormalities and proteins of the MHC, thus implicating the immune system in schizophrenia. Overpruning of dendritic spines coupled with aberrant synaptic plasticity, an essential function for learning and memory, would lead to brain misconnections and synaptic inefficiency underlying the primary negative symptoms and cognitive deficits of schizophrenia. This driving hypothesis has relevant therapeutic implications, including the importance of pharmacological interventions during the prodromal phase or the transition to psychosis, targeting apoptosis, microglia cells or the glutamate storm. Future research on apoptosis and brain integrity should combine brain imaging, CSF biomarkers, animal models and cell biology.
精神分裂症仍然是一个未解之谜。然而，最近从遗传学、分子生物学、神经影像学、动物模型和转化临床研究中获得的综合发现为我们提供了证据，表明需要重新评估精神分裂症的突触修剪过度假说。在神经发育的关键时期，由于兴奋性谷氨酸能锥体细胞和抑制性 GABA 能中间神经元之间的失衡，可能会发生区域性谷氨酸风暴，通过局部树突凋亡机制触发过度的树突修剪。树突棘的凋亡丢失会因小胶质细胞的激活而加剧，这种激活是通过补体异常和 MHC 蛋白的最近描述的信号系统引起的，从而使免疫系统与精神分裂症有关。树突棘的过度修剪与异常的突触可塑性（学习和记忆的基本功能）相结合，会导致大脑连接错误和突触效率低下，从而导致精神分裂症的主要阴性症状和认知缺陷。这一驱动假说具有相关的治疗意义，包括在前驱期或向精神病过渡期间进行药物干预的重要性，以靶向细胞凋亡、小胶质细胞或谷氨酸风暴。关于细胞凋亡和大脑完整性的未来研究应结合脑成像、CSF 生物标志物、动物模型和细胞生物学。
