Regulation of Tau Protein on the Antidepressant Effects of Ketamine in the Chronic Unpredictable Mild Stress Model

Abstract

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.

Tau hyperphosphorylation induced by the anesthetic agent ketamine/xylazine involved the calmodulin‐dependent protein kinase II

“…Another study reported that long‐term administration of ketamine in mice (30 mg/kg for 3 and 6 months) and monkeys (1 mg/kg for 6 months) induced tau hyperphosphorylation at S199, an epitope that was not affected by ketamine/xylazine in our experimental design. A recent study found that chronic unpredictable mild stress was accompanied by tau hyperphosphorylation at S396 and S404, and that ketamine was able to decrease this hyperphosphorylation of tau in the synapses of C57BL/6 mice, which differs from the higher phosphorylation we observed at S396 and S404 following ketamine/xylazine injection. It was also previously reported that the use of ketamine alone decreased CaMKII phosphorylation in the hippocampus and cortex of rats, which is the opposite of what we observed here when using ketamine in combination with xylazine.…”

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

“…Since mice deficient in the serotonin neurotransmitter showed reduced depression-like behavior and chronic administration of the SSRI fluoxetine lead to increased hippocampal neurogenesis [77], this may be a feasible medication to restore neurogenesis in adults. In preclinical and clinical studies a single treatment of the antidepressant ketamine has been sufficient to relieve depressive symptoms in adult patients and C57BL/6 mice previously exposed to chronic stress [78,79]. In humans, ketamine is known to relief symptoms in a very short period of time, but more investigation is needed to ameliorate or prevent associated side effects [79].…”

Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy

“…Combined stress and TBI increased neuroinflammation, axonal injury and behavioral deficits [40]. CVS induces Tau phosphorylation at Ser396 and Ser404 [68]. Unpublished work by one of us (A.F.Z.)…”