A calcineurin inhibitor such as tacrolimus, an immune suppressant drug, has been associated with cognitive decline in organ transplant recipients (1).  Although synaptic plasticity is essential for cognitive function, its alteration following tacrolimus administration remains poorly characterized.  Therefore, this study aimed to evaluate the effects of tacrolimus on synaptic plasticity and cognitive function in normal rats, with a focus on calcineurin-related signaling and synaptic protein alterations.

Thirty-four-week-old male Wistar rats received either vehicle (olive oil, s.c.) or tacrolimus at doses of 0.5, 1.0, or 2.0 mg/kg/day (s.c.) for 2 weeks.  Cognitive performance was assessed using the novel object location and novel object recognition (NOL and NOR) tests.  One day later, rats were euthanized, and the left and right hippocampi were collected for ex vivo long-term potentiation (LTP) recordings and immunoblotting analysis, respectively.

High-dose tacrolimus significantly reduced preference for the novel location, indicating impaired hippocampus-dependent spatial memory. In contrast, preference for the novel object did not differ among groups, suggesting preserved recognition memory.

High-dose tacrolimus markedly reduced the field excitatory postsynaptic potential (fEPSP) slope compared with other groups, indicating impaired synaptic plasticity.

PSD-95 protein expression was significantly reduced in the high-dose tacrolimus group compared with the vehicle group.  Although calcineurin protein expression remained unchanged, FKBP12 expression was significantly increased in all tacrolimus-treated groups.

High-dose tacrolimus impaired hippocampal synaptic plasticity and spatial memory in rats, accompanied by changes in calcineurin-associated pathways.  The findings underscore the importance of optimizing tacrolimus dosing and developing targeted strategies to mitigate neurotoxicity while preserving its immunosuppressive efficacy in clinical settings.