Abstract
Rapamycin inhibits protein translation in cells, including neural stem cells (NSCs), by suppressing the mechanistic target of rapamycin (mTOR). This drug has been widely used together with calcineurin inhibitors in transplantation patients to prevent graft rejection. Previous studies have reported an association between mTOR and depression, but few investigations of this have occurred in transplant recipients. We have here tested the psychiatric effects of rapamycin in mice. The animals treated with rapamycin showed decreased locomotion and sugar consumption. In these rapamycin-treated mice also, the granule cells in the dentate gyrus (DG), which actively differentiate and proliferate from NSC, showed decreases in both excitatory and inhibitory synaptic transmission. Furthermore, the SOX2/NeuN ratio in the DG was decreased in mice treated with rapamycin. We further show that kidney transplantation patients who are receiving rapamycin have more psychiatric disorder such as adjustment disorder. Clinical attention is thus needed when administering rapamycin to transplant recipients due to its behavioral effects and its impact on NSC.
Highlights
Kidney transplantation (KT) is an effective intervention for end-stage renal disease, as the patient no longer requires time-consuming hemodialysis and it prevents chronic renal failure (CRF)
Prior genetic studies have found that the hyperactivation of mechanistic target of rapamycin (mTOR) caused by its upstream modulator phosphatase and tensin homolog (PTEN) deletion and a TSC1 deletion increases the neural stem cells (NSCs) size and number, and augments dendritic spine arborization, synaptic branching, and synaptic excitation[6,7]
Our findings indicate that rapamycin causes behavior and electrophysiological changes, and has negative effects on the proliferation of NSC
Summary
Kidney transplantation (KT) is an effective intervention for end-stage renal disease, as the patient no longer requires time-consuming hemodialysis and it prevents chronic renal failure (CRF). We assessed the effects of rapamycin on psychiatric illness in mouse models using behavioral, electrophysiological, and immunofluorescence methodologies. The mice treated with rapamycin showed a decreased body weight compared with control vehicle-treated animals (Fig. 1a). Immunoblotting of the brain tissue from the rapamycin mouse group showed decreased levels of phospho-S6 kinase, a protein which is activated by mTOR, compared with the control animals (Supplementary Fig. 1).
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