Effects Of FKBP12.6 On Learning And Memory In Mice

Objective:FK506 binding protein 12.6(FKBP12.6), a member of the FKBP protein family, is an intracellular receptor of immunosuppressive agent FK506. FKBP12.6 is consist of 108 amino acid with a 12.6 KD of molecular weight. It can physiologically bind to RyR2 of the endoplasmic reticulum or sarcoplasmic reticulum, keeping the calcium release channel stable and thereby, reducing the endoplasmic reticulum or sarcoplasmic reticulum calcium ion leakage. In addition, FKBP12.6 can inhibit the activity of calcineurin when it forms a complex with FK506, resulting in inhibition of the immune response. FKBP12.6 mainly distributed in heart, brain tissue and smooth muscle and so on. The protein is widely expressed in the central nervous system including regions related with learning and memory such as the hippocampus and amygdala in mice. However, its function in learning and memory is still unclear. Our study was to investigate the role of FKBP12.6 in novel object recognition memory, object location recognition memory and cued fear memory, and to explore the underlying mechanisms. Methods:1. Identify whether FKBP12.6 gene is successfully knocked out by analysis of DNA from mouse tail.2. Compare memory between FKBP12.6-null mice and WT mice in novel object recognition task and object location recognition task based on the animals' spontaneous preference for the novel object and novel location object, respectively.3. Compare cued fear memory between FKBP12.6-null mice and WT mice by fear memory test system based on Pavlovian conditioning principle.4. Compare mEPSP and mIPSP in the amygdala between FKBP12.6-null mice and WT mice by patch clamp recording technique.5. Compare the expression level of c-fos in brain between FKBP12.6-null mice and WT mice by immunohistochemistry. Results:1. FKBP12.6 gene is successfully knocked out.2. Compared with WT mice, novel object recognition memory, object location recognition memory and cued fear memory of FKBP12.6-null mice are impaired.3. Compared with WT mice, there is no obvious difference in the frequency of mIPSP, but the frequency of mEPSP is significantly declined in the amygdala neurons of FKBP12.6-null mice.4. Compared with WT mice, the expression of c-fos is decreased in the amygdala of FKBP12.6-null mice. Conclusions:In the present study, we observed that deletion of FKBP12.6 gene impaired novel object recognition memory, object location recognition memory and cued fear memory in the null mice compared with age-matched wild type mice. Our results indicated that the decline of mEPSP frequency and c-fos expression in amygdala might be correlated with the disruption of cued fear memory in FKBP12.6-null mice.