SirT2 Inhibition is Associated with Improvements in Depression-like Behavior and Memory Impairment in Olfactory Bulbectomized Mice.

Increased silent information regulator protein 2 (SirT2) expression in the prefrontal cortex (PFC) has been reported to be associated with the development of depression; however, its functional contribution to depression-like behavior and memory impairment remains incompletely understood. In this study, we examined alterations in SirT2 expression in the PFC of olfactory bulbectomized (OBX) mice, a well-established model of depression, and evaluated the effects of AK-7, a selective SirT2 inhibitor, on OBX-induced depression-like behavior and memory impairment. On day 21 after surgery, OBX mice exhibited depression-like behaviors and memory impairment, as evidenced by prolonged immobility, reduced sucrose preference and spontaneous alternation, and shortened passive avoidance latency. Expression of SirT2 and pro-inflammatory microglial markers increased significantly, while those of Ac-FoxO1, PPARγ, arginase-1, MBP, MAG, CNPase, and Caspr were decreased, in the PFC of OBX mice. AK-7 administration attenuated these behavioral and molecular alterations. SirT2, Ac-FoxO1, and PPARγ showed spatial overlap with the microglial marker Iba1. AK-7 reduced microglial activation-associated morphological changes and attenuated OBX-induced disruption of node of Ranvier formation. These results suggest that AK-7 administration attenuates depression-like behavior and memory impairment, with concurrent improvements in node of Ranvier organization and modulation of microglial polarization in the PFC. Furthermore, our findings suggest that dysregulated SirT2 signaling may be involved, at least in part, in the development of depression-like behavior and comorbid memory impairment, and represents a potential avenue for further investigation.