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

我们的目标是开发基于疾病分子机制的发育障碍的新的治疗和诊断方法。在这项研究中，我们分析了1)缺乏智力低下基因motopsin(Prs12)的小鼠的行为表型，以及2)motopsin相互作用蛋白SEZ6的时空定位。一项社会记忆测试没有发现异常，然而，突变的小鼠对一只陌生的小鼠表现出长时间的嗅觉。在一项社会新颖性测试中，运动素缺乏的小鼠即使对熟悉的小鼠也表现出长期的兴趣。与这些行为缺陷相一致的是，锥体神经元顶端树突上的脊椎密度在海马CA1区显著降低，这是已知的对空间记忆和社会行为至关重要的区域。我们先前发现SEZ6是一个运动素结合蛋白。用重组SEZ6蛋白制备的抗SEZ6抗体检测大鼠海马CA1区、大脑皮层、杏仁外侧核和尾壳核的SEZ6免疫反应(IR)。在出生后第7天的大脑皮层和出生后第10天的CA1海马区有明显的SEZ6免疫反应，提示这些区域与MOTOPIN相互作用。在人脑和脊髓中也观察到了类似的定位。我们的结果表明，神经细胞分泌的Motopsin锚定在神经元上的SEZ6蛋白上，缺乏Motopsin功能会导致一些智力低下的症状，如记忆形成障碍和社会行为异常，通过海马体功能的缺陷。

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.