Tau phosphorylation in the mouse brain during aversive conditioning.

Stress response is intimately involved in memory formation. Stress has been shown to cause reversible Alzheimer-like tau phosphorylation in the brain of experimental animals, but it is not known whether tau phoshorylation takes place during memory acquisition. As an initial investigation we chose contextual fear conditioning paradigm involving electric shocks, and studied tau phosphorylation in the hippocampus and a neighboring limbic region of the mouse brain. Quantitative immunoblot analyses of tissue extracts rapidly prepared from animals undergoing the conditioning showed statistically significant increases in the phosphorylation level at Thr231/Ser235 of tau in both tissues. The reaction reached statistical significance after 10 but not 3 shocks of 0.8mA. Ten shocks of 0.2mA were ineffective. Concurrent increases in phosphorylation of protein kinase TPKI/GSK3beta at Ser9 and of CaMKIIalpha at Thr286 were observed. These results suggest involvement of tau and TPKI/GSK3beta phosphorylation in an early phase of memory formation in the hippocampus and amygdala, raising a possibility that a dysregulation of tau phosphorylation may underlie memory impairment in incipient Alzheimer's disease.