Sodium butyrate, a histone deacetylase Inhibitor, ameliorates SIRT2-induced memory impairment, reduction of cell proliferation, and neuroblast differentiation in the dentate gyrus

Abstract

Objectives:

Histone deacetylases (HDACs) play a key role in synaptic plasticity and learning and memory. Sirtuin 2 (SIRT2), a class III HDAC, is abundantly expressed in neurons and functions as a mitotic exit regulator in dividing cells. In this study, we investigated the role of SIRT2 in cell proliferation and neuroblast differentiation in the mouse dentate gyrus.

Methods:

To facilitate the delivery of SIRT2 into neurons, we constructed a PEP-1-SIRT2 fusion protein. Mice were divided into three groups: vehicle (PEP-1), SIRT2, and SIRT2 with sodium butyrate (an HDAC inhibitor). PEP-1 or PEP-1-SIRT2 fusion protein was administered intraperitoneally to 7-week-old mice once a day for 3 weeks, and the mice were killed 2 h after the last administration. Sodium butyrate, an HDAC inhibitor, was subcutaneously administered in parallel with PEP-1-SIRT2 once a day for 3 weeks.

Results:

The administration of PEP-1-SIRT2 alone significantly reduced the time spent exploring a new object in the novel object recognition test, whereas treatment with sodium butyrate increased the time spent exploring a new object. Results of Ki67 and doublecortin immunohistochemistry revealed that the administration of PEP-1-SIRT2 significantly reduced cell proliferation and neuroblast differentiation, respectively, in the dentate gyrus. However, the administration of sodium butyrate significantly ameliorated the SIRT2-induced reduction in cell proliferation and neuroblast differentiation.

Conclusion:

This result suggests that histone acetylation and deacetylation are key factors modulating hippocampal functions such as memory formation, cell proliferation, and neuroblast differentiation in the dentate gyrus.

Keywords:

• Sirtuin 2
• Sodium butyrate
• Histone deacetylation
• Neurogenesis
• Dentate gyrus

Acknowledgements

This work was supported by Priority Research Centers Program through the National Research Foundation of Korea (Grant No. NRF-2009-0093812).