Mice with the Rab10 T73V mutation exhibit anxiety-like behavior and alteration of neuronal functions in the striatum

Hyperphosphorylated Rab10 has been implicated in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. However, the neurophysiological function of the evolutionarily conserved Thr73 phosphorylation of Rab10 remains poorly understood. Here, we generated a novel mouse model expressing the non-phosphorylatable T73V mutation of Rab10 and performed a comprehensive series of neurological analyses, including behavioral tests, synaptic evaluations, neuronal and glial staining, assessments of neurite arborization and spine morphogenesis. The Rab10 T73V mutantmice exhibited a characteristic anxiety-like phenotype with other behavioral modules relatively unaffected. Moreover, Rab10 T73V mutant mice displayed striatum-specific synaptic dysfunction, as indicated by aberrantly increased expression levels of synaptic proteins and impaired frequencies of miniature inhibitory postsynaptic currents. The genetic deletion of Rab10 phosphorylation enhanced neurite arborization and accelerated spine maturation in striatal medium spiny neurons. Our findings emphasize the specific role of intrinsic phospho-Rab10 in the regulation of the striatal circuitry and its related behaviors.