Abstract
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.