Elevated contextual fear memory by SIRT6 depletion in excitatory neurons of mouse forebrain

A class of NAD-dependent protein deacetylases, the Sirtuin (SIRT) family of proteins is involved in aging, cell survival, and neurodegeneration. Recently, SIRT proteins, including SIRT6, have been reported to be important in learning and memory. However, the role of SIRT6 in excitatory brain neurons in cognitive behaviors is not well characterized. We investigated how cognitive behaviors are affected by genetic SIRT6 depletion in excitatory neurons in the mouse forebrain. We generated a conditional knockout (cKO) mouse line by mating two transgenic lines, Floxed SIRT6 and CaMKIIa-Cre. SIRT6 was thus deleted by Cre recombinase in CaMKIIa-expressing excitatory neurons. We performed cognitive behavioral tests, focusing on learning and memory, including contextual fear conditioning and Morris-water maze. The freezing level of SIRT6 cKO before the fear conditioning was comparable to that of wild-type littermate controls, while the freezing level after the conditioning was higher in SIRT6 cKO mice. In contrast, the mice showed normal spatial learning and memory in the Morris-water maze. In addition, anxiety and locomotion were also normal in SIRT6 cKO mice. SIRT6 genetic depletion enhanced contextual fear memory without affecting spatial memory. Since a previous report showed that overexpression of SIRT6 reduced contextual fear memory, our results suggest that the expression level of SIRT6 bi-directionally regulates contextual fear memory in mice.