Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens.
Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens.
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DOI：
10.1126/scitranslmed.3001079
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发表时间：
2010-10-20
影响因子：
17.1
通讯作者：
Kaplitt MG
中科院分区：
文献类型：
--
作者：
Alexander B;Warner-Schmidt J;Eriksson T;Tamminga C;Arango-Lievano M;Ghose S;Vernov M;Stavarache M;Musatov S;Flajolet M;Svenningsson P;Greengard P;Kaplitt MG
重性抑郁症的病因仍不清楚，但长期以来，多巴胺能信号传导功能障碍与这种疾病的病理生理学有关。p11是S100家族成员，最近被鉴定为5-羟色胺1B（5-HT 1B）和5-羟色胺4（5-HT 4）受体结合蛋白。p11缺失的突变小鼠表现出抑郁样行为，表明p11可能是情感障碍病理生理学的介导者。使用体细胞基因转移，我们现在已经确定了核的p11行动的一个关键位点的核（NAcc）。腺相关病毒（AAV）介导的RNA干扰（RNAi）在NAcc中减少p11，但在正常成年小鼠的前扣带回中没有减少，导致与p11敲除小鼠几乎相同的抑郁样行为。p11基因敲除小鼠NAcc中p11表达的恢复使抑郁样行为正常化。与匹配的健康对照相比，人类NAcc组织显示抑郁症患者中p11蛋白的显著减少。这些结果表明，在啮齿动物和人类NAcc的p11损失可能有助于抑郁症的病理生理。用AAV介导的基因治疗使该脑区域内的p11表达正常化可能具有治疗价值。
The etiology of major depression remains unknown, but dysfunction of serotonergic signaling has long been implicated in the pathophysiology of this disorder. p11 is an S100 family member recently identified as a serotonin 1B (5-HT1B) and serotonin 4 (5-HT4) receptor binding protein. Mutant mice in which p11 is deleted show depression-like behaviors, suggesting that p11 may be a mediator of affective disorder pathophysiology. Using somatic gene transfer, we have now identified the nucleus accumbens (NAcc) as a key site of p11 action. Reduction of p11 with adeno-associated virus (AAV)-mediated RNA interference (RNAi) in the NAcc, but not in the anterior cingulate, of normal adult mice resulted in depression-like behaviors nearly identical to those seen in p11 knockout mice. Restoration of p11 expression specifically in the NAcc of p11 knockout mice normalized depression-like behaviors. Human NAcc tissue shows a significant reduction of p11 protein in depressed patients when compared to matched healthy controls. These results suggest that p11 loss in rodent and human NAcc may contribute to the pathophysiology of depression. Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value.
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影响因子：
30.8
作者：
KAPLITT, MG;LEONE, P;DURING, MJ
通讯作者：
DURING, MJ
影响因子：
10.6
作者：
Gutman, David A.;Holtzheimer, Paul E.;Behrens, Timothy E. J.;Johansen-Berg, Heidi;Mayberg, Helen S.
通讯作者：
Mayberg, Helen S.
影响因子：
4.2
作者：
Worgall, Stefan;Sondhi, Dolan;Crystal, Ronald G.
通讯作者：
Crystal, Ronald G.
影响因子：
16.2
作者：
Mayberg, HS;Lozano, AM;Kennedy, SH
通讯作者：
Kennedy, SH
DOI：
10.1073/pnas.0711839105
发表时间：
2008-02-12
影响因子：
11.1
作者：
Zhang, Xiaoqun;Andren, Per E.;Svenningsson, Per
通讯作者：
Svenningsson, Per