Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Neuron. 2023 Nov 1;111(21):3378-3396.e9. doi: 10.1016/j.neuron.2023.08.004. Epub 2023 Aug 31.
A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ.
一个具有遗传有效性的动物模型可以改变我们对精神分裂症（SCZ）疾病机制的理解。编码 NMDA 受体亚单位的 GRIN2A 中罕见的杂合性丧失功能（LoF）突变大大增加了 SCZ 的风险。通过转录组、蛋白质组和行为分析，我们报告杂合 Grin2a 突变小鼠表现出：（1）多个脑区和神经元（兴奋性和抑制性）和非神经元细胞（星形胶质细胞和少突胶质细胞）中大规模的基因表达变化；（2）前额叶皮层（PFC）活动减少和海马体和纹状体过度活跃的证据；（3）纹状体中多巴胺信号升高和安非他命诱导的过度活跃（AIH）敏感性增加；（4）星形胶质细胞中胆固醇生物合成的改变；（5）突触中谷氨酸能受体信号蛋白减少；以及（6）与抗精神病药物诱导的运动模式相反的异常运动模式。这些发现揭示了潜在的病理生理机制，为 SCZ 的“低谷氨酸”和“高多巴胺”假说提供了支持，并强调了 Grin2a 缺陷小鼠作为 SCZ 遗传模型的实用性。
