Deficiency of Rab26 causes behavioral defects in mice through impaired trafficking of serotonin (5-HT) transporter

Rab proteins are key regulators of membrane trafficking. Dysregulated Rab proteins are associated with neurological diseases through the regulation of receptor endocytosis, recycling, and/or degradation. Rab26 is highly expressed in the brain, but its physiological function remains poorly elucidated. Here we demonstrate that Rab26 deficiency in mice causes depression and anxiety-like behaviors and cognitive impairment. The depletion of Rab26 results in the accumulation of synaptic vesicles in the presynaptic terminals and a decrease in the frequency of miniature excitatory postsynaptic currents (mEPSCs) and long-term potentiation (LTP). Mechanistically, Rab26 regulates the trafficking of serotonin (5-HT) transporter (SERT/Slc6a4). Rab26 interacts with SERT and promotes the autophagic degradation of SERT. Loss of Rab26 results in increased cell surface levels of SERT, suggesting that Rab26 plays a role in regulating the trafficking of SERT to maintain normal serotonin-mediated neurotransmission.