Genetic mutations in the gene encoding transport protein particle complex 9 (trappc9), a subunit of TRAPP that acts as a guanine nucleotide exchange factor for rab proteins, cause intellectual disability with brain structural malformations by elusive mechanisms. Here, we report that trappc9-deficient mice exhibit a broad range of behavioral deficits and postnatal delay in growth of the brain. Contrary to volume decline of various brain structures, the striatum of trappc9 null mice was enlarged. An imbalance existed between dopamine D1 and D2 receptor containing neurons in the brain of trappc9-deficient mice; pharmacological manipulation of dopamine receptors improved performances of trappc9 null mice to levels of wild-type mice on cognitive tasks. Loss of trappc9 compromised the activation of rab11 in the brain and resulted in retardation of endocytic receptor recycling in neurons. Our study elicits a pathogenic mechanism and a potential treatment for trappc9-linked disorders including intellectual disability.

编码转运蛋白颗粒复合物 9 (tappc9) 的基因中的基因突变是 TRAPP 的一个亚基，可作为 rab 蛋白的鸟嘌呤核苷酸交换因子，通过难以捉摸的机制导致智力障碍和脑结构畸形。在这里，我们报告 trappc9 缺陷小鼠表现出广泛的行为缺陷和大脑生长的出生后延迟。与各种脑结构体积下降相反，trappc9 缺失小鼠的纹状体增大。trappc9缺陷小鼠脑内含多巴胺D1和D2受体的神经元存在失衡；多巴胺受体的药理学操作将 trappc9 缺失小鼠的认知任务提高到野生型小鼠的水平。trappc9 的缺失损害了大脑中 rab11 的激活，并导致神经元内吞受体循环的延迟。我们的研究引发了一种致病机制和一种潜在的治疗 trappc9 相关疾病（包括智力障碍）的方法。