The results of this study are consistent with prior findings in 3xTg-AD mice showing age-dependent increases in Tau AT8 expression. Untreated 3xTg-AD mice show low levels of pTau AT8 immunoreactivity the HPC (CA1 region) at 6months of age but prominent expression in neurons and projections at 15months of age (Oddo, Caccamo, Kitazawa, et al., 2003). This age-dependent progression of AT8 expression is similar to the present result showing that alcohol drinking (1-month post exposure) was associated with hyperphosphorylation of Tau at the Ser199/202 residues in the HPC. As noted above, Tau phosphorylation at these sites in humans is associated with advanced Braak stage V/VI Alzheimer’s disease that is characterized by severe dementia and other neuropsychiatric symptoms. This raises the possibility that alcohol-induced upregulation of GSK3β phosphorylation of Tau (Ser199/202) may mediate hippocampal-dependent behavioral pathology associated with alcohol use. Indeed, the present results show that alcohol-exposed 3xTg-AD mice have deficits in spatial memory (Fig. 5A) and sensorimotor gating (PPI, Fig. 5B), which are both modulated by hippocampal activity. It is also interesting to note that there was no difference in pTau
