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Tau protein is known to play an important role in maintaining microtubule assembly and stabilization, and maintaining the normal morphology of neurons, but several studies have found that chronic stress leads to Tau hyperphosphorylation. A large number of clinical trials have found that ketamine, which is an N-methyl-D-aspartate receptor antagonist, produces a rapid, long-lasting, and potent antidepressant effect in patients suffering from major depression. This rapid antidepressant effect of ketamine, which involves many mechanisms, has attracted wide attention. However, the relationship between ketamine’s antidepressant effects and Tau protein has rarely been examined. We used C57BL/6 and Tau KO mice exposed to 42 days of chronic unpredictable mild stress (the CUMS model) to investigate the effect of ketamine on behavioral changes and synaptic functioning of the hippocampus. The results showed that a single treatment of ketamine rapidly relieved the CUMS-induced anhedonia, depression-like, and anxious behaviors of the C57BL/6 mice. The abnormal behaviors were accompanied by increased levels of specific alterations of hyperphosphorylated Tau protein in cytoplasm and synapse in the hippocampus of the C57BL/6 mice, but ketamine reduced the aggregation of hyperphosphorylated Tau protein only in the synapse. We also found that CUMS exposure reduced the levels of GluA1 and PSD95 in the hippocampus of the C57BL/6 mice and that these deficits were reversed by ketamine. However, the Tau KO mice did not develop any stress-induced depressive behaviors or deficits of hippocampal function. The antidepressant effect of ketamine may decrease the levels of hyperphosphorylated Tau protein in synapse of C57BL/6 mice.

The monocarboxylate transporters (MCTs) MCT1, MCT2, and MCT4 are essential components of the astrocyte-neuron lactate shuttle (ANLS), which is a fundamental element of brain energetics. Decreased expression of MCTs can induce cognitive dysfunction of the brain. In the present study, we established a mouse model of long-term ketamine administration by subjecting mice to a 6-month course of a daily intraperitoneal injection of ketamine. These mice demonstrated learning and memory deficits and a significant decline in MCT1 and MCT4 proteins in the hippocampal membrane fraction, while cytoplasmic MCT1 and MCT4 protein levels were significantly increased. In contrast, the levels of global MCT2 protein were significantly increased. Analysis of mRNA levels found no changes in MCT1/4 transcripts, although the expression of MCT2 mRNA was significantly increased. We suggest that redistribution of hippocampal MCT1 and MCT4, but not MCT2 up-regulation, may be related to learning and memory deficits induced by long-term ketamine administration.

Long‐term ketamine abuse can cause significant lower urinary tract symptoms in humans, termed ketamine‐associated cystitis (KC). Here, we established a model of long‐term (6 months) ketamine administration in wild‐type (C57BL/6) mice. We elucidated the pathological effects of ketamine in the bladder and investigated changes in autophagy‐associated protein expression (i.e., LC3, Beclin‐1, and P62) and inflammatory cytokines (i.e., IL‐6 and IL‐1β) in the bladder smooth muscle tissue. Long‐term ketamine administration reduced the number of layers in the bladder mucosal epithelial cells (4–5 layers in the saline group vs. 2–3 layers in the ketamine groups), but increased the number of mast cells and collagen fibers. LC3‐II/LC3‐I, Beclin‐1, IL‐6, and IL‐1β protein expression in the bladder smooth muscle tissues of ketamine‐treated mice was significantly increased. The mRNA and protein levels of P62 in the Ket‐60 mg/kg group were also significantly increased, but not the Ket‐30 mg/kg group. Our results reveal that long‐term ketamine administration can cause cystitis‐like pathological changes in mice, and the disordered autophagy in the bladder tissue may be involved in the persistent bladder damage following long‐term administration of ketamine at 60 mg/kg.

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