RNA interference-mediated phosphodiesterase-4D knockdown in the prefrontal cortex elicits antidepressant-like and cognitive-enhancing behaviors via increased cyclic AMP signaling in mice
作者单位：University of South Carolina School of MedicineColumbia SC 29208USA
会议名称：《中国药理学会第十一次全国学术会议》
会议日期：2011年
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
基 金：The project supported by National Natural Science Foundation of China(30973515 81072624) the National Basic Research Program of China(2007CB512307) the National Key Technology R&D Program of China Program of China(2008AA02Z402)
关 键 词：phosphodiesterase 4D RNA interference antidepressant cognitive prefrontal cortex
摘 要：OBJECTIVE Phosphodiesterase 4(PDE4),specific for cyclic AMP(cAMP)-hydrolyzing,has four isoforms (PDE4A-D) with at least 25 splice ***4 inhibitors produce definite antidepressant-like and cognitive-enhancing effects. However,none of PDE4 inhibitors has yet been approved for clinical utility so far due to the concomitant side effects which appear to be PDE4 isoform *** present research is to explore the major isoforms of PDE4 responsible for antidepressant-like and cognitive-enhancing effects of PDE4 inhibitors but not side *** Long-form PDE4Ds were silenced by the bilateral microinfusion of lentiviral vector containing miRNAs(4DmiR) into the prefrontal cortex(PFC).The expression of the miRNAs,which were indicated by EGFP,was identified using fluorescence ***-like behaviors were measured by tail-suspension test (TST),forced swimming test(FST) and chronic unpredictable stress *** and memory behaviors were measured by novel object recognition test(NOR) and Morris water maze test(MWM) in both normal mice and the mice with chronic unpredictable stress-induced memory *** emetic potential was evaluated by the assessment of the anaesthetic reversal effect,a surrogate of the emesis test in non-vomiting *** expressions of PDE4 isoforms/splice variants and cAMP signaling related proteins in PFC were examined by Western-blot ***(1) High and specific expression of EGFP(green) in PFC was observed under fluo-rescence microscopy.(2) 4DmiR significantly down-regulated PDE4D4/5 splice variants,but not PDE4A,PDE4B or PDE4D1/2/3. (3) 4DmiR treatments significantly increased cAMP,pCREB and BDNF in PFC.(4) Rolipram and/or4DmiR treatments significantly decreased immobility in TST and FST.(5) Rolipram and/or 4DmiR treatments reversed the depressive-like behaviors in chronically stressed mice,including the reduced sucrose preference,prolonged latency to novelty-suppressed feeding and increased immobi