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FKBP12.6 and cADPR are two regulators of ryanodine Ca2 release receptors which play a pivotal role in the regulation of numerous cellular functions.The current study was designed to examine the effect of FKBP12.6 and ADP-ribosyl cyclase (ADPRclase, a key regulator of endogenous cADPR production) on the function of hippocampus.In this study, both FKBP12.6 knockout and wild 129 mice (8-12 week old) were divided into three groups respectively: control group, mice were given a 7 day continuous infusion of 0.9% NaCl;DHAB group, mice were given a 7 day continuous infusion of 2,2-dihydroxyazobenzene (DHAB, a ADPRclase inhibitor, 2 mg/kg·day-1);cADPR group, mice were given a 7 day continuous infusion of exogenous cADPR (1mg/kg·day-1) intraperitoneally.On the 7th day, abilities of learning and memory of the mice were tested by using the Morris water maze and space experiments.The expression of ADPRclase mRNA and protein in hippocampus of mice were detected by using RT-PCR and Western Blotting respectively.The Morris water maze and space experiments revealed that the abilities of learning and memory were decreased significantly in FKBP1 2.6 knockout mice and DHAB treated wild 129 mice.The abilities decrease was aggravated by DHAB and alleviated by exogenous cADPR in FKBP12.6 knockout mice.Expression of mRNA and protein of ADPRclase was lower in FKBP12.6 knockout mice than that in wild mice.DHAB inhibited the expression of ADPRclase in both FKBP12.6knockout and wild mice.These data shows that ADPRclase expression was decreased by FKBP12.6 knockout and FKBP 12.6/ADPRclase/cADPR may maintain the function of hippocampus in mice.