Basic research for understanding the molecular mechanism of mental retardation and the development of the treatment and diagnostic methods for the disease.

我们的目标是基于疾病的分子机制开发新的治疗和诊断方法。在这项研究中，我们分析了1)缺乏智力迟钝基因motopsin （prss12）的小鼠的行为表型，以及2)motopsin相互作用蛋白SEZ6的时空定位。motopsin缺乏小鼠表现出中度空间记忆受损。社会记忆测试没有发现异常，但突变小鼠对陌生小鼠表现出长时间的嗅探。在社交新颖性测试中，缺乏运动肽的老鼠即使对熟悉的老鼠也表现出持久的兴趣。与这种行为缺陷相一致的是，海马CA1区锥体神经元顶端树突棘密度显著降低，而CA1区是空间记忆和社会行为的关键区域。我们之前已经鉴定出SEZ6是一种运动蛋白酶结合蛋白。采用重组SEZ6蛋白制备的抗SEZ6抗体检测海马CA1区、大脑皮层、外侧杏仁核和尾状壳核的SEZ6免疫反应性（IR）。我们注意到，SEZ6 IR在出生后第7天的大脑皮层和P10的CA1海马中明显存在，表明这些区域与motopsin相互作用。在人脑和脊髓中也观察到类似的定位。我们的研究结果表明，神经元细胞分泌的motopsin锚定在神经元上的SEZ6蛋白上，缺乏motopsin功能通过海马功能缺陷导致一些智力迟钝的症状，如记忆形成障碍和社会行为异常。

Our aim is the development of novel therapy and diagnostic method for developmental disorders based on the molecular mechanism of the disease. In this study, we analyzed 1) the behavioral phonotype of mice lacking a mental retardation gene, motopsin (prss12), and 2) spatio-temporal localization of a motopsin-interacting protein, SEZ6.Motopsin-deficient mice showed moderately impaired spatial memory. A social memory test failed to reveal abnormality, however, the mutant mice showed prolonged sniffing to a stranger mouse. In a social novelty test, motopsin-deficient mice showed prolonged interest even in a familiar mouse. Consistent with such behavioral deficits, the spine density on apical dendrites of pyramidal neurons was significantly decreased at hippocampus CA1 region, which is known to be crucial for spatial memory and social behavior.We have previously identified SEZ6 as a motopsin-binding protein. SEZ6 immunoreactivity (IR) was detected at the hippocampal CA1 region, cerebral cortex, lateral amygdala, and caudate putamen using anti-SEZ6 antibody, which was prepared against recombinant SEZ6 protein. It was noted that SEZ6 IR was obvious in the cerebral cortex at postnatal day (P) 7 and the CA1 hippocampus at P10, suggesting interaction with motopsin in these regions. Similar localization was observed in the human brain and spinal cord.Our results suggest that motopsin secreted from neuronal cells anchors to SEZ6 proteins on neurons and that lack of motopsin function causes some symptom of mental retardation, eg, impaired memory formation and abnormal social behavior, through the defect of hippocampal function.