Schizophrenia is associated with cognitive and behavioral dysfunctions thought to reflect imbalances in neurotransmission systems. Recent screenings suggested that lack of (functional) syndapin I (PACSIN1) may be linked to schizophrenia. We therefore studied syndapin I KO mice to address the suggested causal relationship to schizophrenia and to analyze associated molecular, cellular, and neurophysiological defects. Syndapin I knockout (KO) mice developed schizophrenia-related behaviors, such as hyperactivity, reduced anxiety, reduced response to social novelty, and an exaggerated novel object response and exhibited defects in dendritic arborization in the cortex. Neuromorphogenic deficits were also observed for a schizophrenia-associated syndapin I mutant in cultured neurons and coincided with a lack of syndapin I–mediated membrane recruitment of cytoskeletal effectors. Syndapin I KO furthermore caused glutamatergic hypofunctions. Syndapin I regulated both AMPAR and NMDAR availabilities at synapses during basal synaptic activity and during synaptic plasticity—particularly striking were a complete lack of long-term potentiation and defects in long-term depression in syndapin I KO mice. These synaptic plasticity defects coincided with alterations of postsynaptic actin dynamics, synaptic GluA1 clustering, and GluA1 mobility. Both GluA1 and GluA2 were not appropriately internalized. Summarized, syndapin I KO led to schizophrenia-like behavior, and our analyses uncovered associated molecular and cellular mechanisms.

中文翻译：

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Syndapin I 在小鼠中的功能丧失导致精神分裂症样症状。

精神分裂症与认知和行为功能障碍有关，被认为反映了神经传递系统的失衡。最近的筛查表明，（功能性）syndapin I (PACSIN1) 的缺乏可能与精神分裂症有关。因此，我们研究了 Syndapin I KO 小鼠，以解决与精神分裂症的建议因果关系，并分析相关的分子、细胞和神经生理学缺陷。Syndapin I 基因敲除 (KO) 小鼠出现精神分裂症相关行为，例如多动症、焦虑减少、对社交新奇事物的反应减弱以及夸大的新事物反应，并表现出皮层树突状树枝化的缺陷。在培养的神经元中也观察到了精神分裂症相关的 Syndapin I 突变体的神经形态发生缺陷，并且与缺乏 Syndapin I 介导的细胞骨架效应器的膜募集相吻合。Syndapin I KO 还导致谷氨酸能机能减退。Syndapin I 在基础突触活动和突触可塑性期间调节突触的 AMPAR 和 NMDAR 可用性——特别引人注目的是，在 Syndapin I KO 小鼠中完全缺乏长期增强作用和长期抑制缺陷。这些突触可塑性缺陷与突触后肌动蛋白动力学、突触 GluA1 聚类和 GluA1 流动性的改变相吻合。GluA1 和 GluA2 都没有被适当地内化。综上所述，syndapin I KO 导致精神分裂症样行为，