Abstract
Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into theCA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long-term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway.
Highlights
The Histone deacetylases (HDACs) family is comprised of Class I (HDAC1, 2, 3 and 8), class II a (HDAC, 5, 7 and 9), II b (HDAC 6 and 10), III and class IV (HDAC 11) enzymes[13]
The analysis of the Western blot data using one-way Analysis of variance (ANOVA) revealed that SIRT6 expression in the CA1 was significantly increased 10 days after lentivirus infection in the group infused with LVSIRT6-GFP (198.2 ± 15.1%) compared with the group infused with LVGFP (100 ± 2.1%) in the CA1 (F1,9 = 41.412, p < 0.0001, Effect size (ES) = 2.035; Fig. 2C and Fig. S2)
The results revealed that all rats formed long-term memory 24 hrs after contextual fear conditioning (Fig. 4B) and intra-CA1 infusion of LVSIRT6-GFP after fear conditioning had no significant effects on the expression and maintenance of contextual fear memory (Fig. 4C)
Summary
The Histone deacetylases (HDACs) family is comprised of Class I (HDAC1, 2, 3 and 8), class II a (HDAC, 5, 7 and 9), II b (HDAC 6 and 10), III (the sirtuins) and class IV (HDAC 11) enzymes[13]. Growing evidence indicates that HDACs are powerful modulators of long-term potentiation (LTP) as well as memory formation[14,15,16]. Increased histone-tail acetylation facilitates various types of long-term memories, including hippocampus-dependent www.nature.com/scientificreports/. SIRT1 has been the most extensively studied, and accumulating evidence suggests that SIRT1 plays a protective role in normal brain physiology and neurological disorders. SIRT6 negatively controls insulin-like factor (IGF)/Akt signaling at the level of chromatin and culminates in the development of cardiac hypertrophy and heart failure in mice. The role of SIRT6 in the formation of contextual fear memory is unknown. In the present study, using a lentivirus-mediated SIRT6 overexpression procedure, we investigated the effect of SIRT6 in the CA1 region on the formation of contextual fear memory and the underlying mechanism
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