NPTX2, Homeostatic Scaling, and Schizophrenia

Schizophrenia is a complex genetic and developmental disorder. We present a model of disease resulting from disruption of a specific stage of homeostatic scaling (HS). HS modifies synapses and circuits in response to changes in neuronal activity and underlies cortical development and memory consolidation. Neuronal pentraxin 2 (NPTX2) plays a critical role in HS and its homeostatic action requires exocytosis at excitatory synapses on parvalbumin interneurons (PV) whereupon a portion is later shed into the CSF. CSF NPTX2 is reduced in two independent cohorts of patients with schizophrenia. To understand the relationship of this biomarker to disease we confirmed that in normal volunteers CSF NPTX2 increases rapidly with sleep deprivation consistent with behavior-linked exocytosis/shedding. In mouse neocortex NPTX2 exocytosis/shedding are activity-dependent and coupled to circadian behavioral. By contrast, in mouse genetic models that interrupt early events in HS NPTX2 exocytosis/shedding are erratic and not linked to behavior. The vital contribution of NPTX2 to homeostasis is revealed in Nptx2-/- mice, which exhibit sensitivity to social isolation stress and multiple schizophrenia-domain phenotypes. NPTX2 is not implicated by human genome studies; rather we propose that diverse mutations linked to schizophrenia disrupt activity-dependent mechanisms required for NPTX2 function. The ability to monitor NPTX2 in human subjects provides an opportunity to translate fundamental neuroscience to human neuropsychiatric disease. Parvalbumin interneuron-specific ribosome-associated mRNA profiles of wild-type and Nptx2 KO mice were generated by RiboTag pulldown and deep sequencing.Three biological replicates were analyzed for each of 4 conditions (two genotypes; two treatments per genotype)精神分裂症（Schizophrenia）是一类复杂的遗传发育性疾病。本研究构建了一种由稳态缩放（homeostatic scaling, HS）特定阶段紊乱所导致的疾病模型。稳态缩放可响应神经元活动变化修饰突触与神经环路，是大脑皮质发育与记忆巩固的分子基础。神经元五聚体蛋白2（neuronal pentraxin 2, NPTX2）在稳态缩放过程中发挥关键调控作用，其稳态调节功能需要在小白蛋白中间神经元（parvalbumin interneurons, PV）的兴奋性突触处发生胞吐作用，随后部分蛋白会被释放至脑脊液（cerebrospinal fluid, CSF）中。在两个独立的精神分裂症患者队列中，脑脊液NPTX2水平均显著降低。为明确该生物标志物与疾病的关联，我们证实：在健康志愿者中，脑脊液NPTX2水平会随睡眠剥夺快速升高，这一现象与行为关联的胞吐/释放过程相一致。在小鼠新皮层中，NPTX2的胞吐与释放过程呈活动依赖性，并与昼夜行为节律相耦合。与之相反，在干扰稳态缩放早期事件的小鼠遗传模型中，NPTX2的胞吐与释放过程呈现紊乱状态，且与行为无明显关联。Nptx2基因敲除（Nptx2-/-）小鼠展现出对社交隔离应激的易感性以及多种精神分裂症相关表型，这揭示了NPTX2在机体稳态调节中的核心作用。人类基因组研究并未直接将NPTX2与精神分裂症相关联；相反，我们提出：与精神分裂症相关的多种突变，会破坏NPTX2功能所需的活动依赖性调控机制。可在人类受试者中监测NPTX2水平的技术手段，为将基础神经科学研究成果转化应用于人类神经精神疾病领域提供了重要契机。本研究通过RiboTag pulldown与深度测序技术，获取了野生型与Nptx2敲除（Nptx2 KO）小鼠的小白蛋白中间神经元特异性核糖体关联mRNA表达谱。针对4组实验条件（两种基因型；每种基因型设置两种处理方式），每组均设置3个生物学重复样本进行分析。