Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome.
Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome.
复制标题
DOI：
10.1038/tp.2012.70
复制
发表时间：
2012-08-07
影响因子：
6.8
通讯作者：
Tanigaki K
中科院分区：
文献类型：
--
作者：
Kimoto S;Muraki K;Toritsuka M;Mugikura S;Kajiwara K;Kishimoto T;Illingworth E;Tanigaki K
22q11.2微缺失是精神分裂症的最高遗传危险因素之一。目前尚不清楚哪些22q11.2区域缺失基因的相互作用是精神分裂症发病机制的原因，但儿茶酚-O-甲基转移酶（COMT）是候选者之一。Df 1/+小鼠是22q11.2缺失综合征（22 q11 DS）模型小鼠，在22 q11相关区域中具有18个基因的半合子缺失。Df 1/+小鼠对多巴胺D1激动剂SKF 38393和N-甲基-D-天冬氨酸拮抗剂MK 801的反应增强，可通过GABAA受体激动剂布他西尼或GABAA α2/α3受体激动剂SL 651498恢复正常。在这里，我们证明了病毒介导的Comt重新引入Df 1/+小鼠的前额叶皮层（PFC）的治疗效果。相反，Comt过表达和Comt抑制均引起对照小鼠对GABAA受体激动剂Bretazenil的异常反应。Comt过表达增加MK 801诱导的PFC神经元间激活和GABA释放，GABA相关基因如Gabrb 2（GABA A受体β2），Gad2结果表明，Comt介导的GABA能系统的调节可能参与了Df 1/+的行为发病机制小鼠
The 22q11.2 microdeletion is one of the highest genetic risk factors for schizophrenia. It is not well understood which interactions of deleted genes in 22q11.2 regions are responsible for the pathogenesis of schizophrenia, but catechol-O-methytransferase (COMT) is among the candidates. Df1/+ mice are 22q11.2 deletion syndrome (22q11DS) model mice with a hemizygous deletion of 18 genes in the 22q11-related region. Df1/+ mice showed enhanced response to the dopamine D1 agonist, SKF38393, and the N-methyl-D-aspartate antagonist, MK801, which can be normalized by a GABAA receptor agonist, bretazenil, or a GABAA α2/α3 receptor agonist, SL651498. Here, we demonstrated the curing effects of virus-mediated reintroduction of Comt to the prefrontal cortex (PFC) in Df1/+ mice. In contrast, both Comt overexpression and Comt inhibition caused an abnormal responsiveness to Bretazenil, a GABAA receptor agonist in control mice. Comt overexpression increased MK801-induced interneuronal activation and GABA release in the PFC. The expression levels of GABA-related genes such as Gabrb2 (GABAAreceptor β2), Gad2 (glutamic acid decarboxylase 65 (Gad65)) and Reln (Reelin) correlate with a Comt expression level in PFC. Our data suggest that Comt-mediated regulation of GABAergic system might be involved in the behavioral pathogenesis of Df1/+ mice.
登录
查看更多内容
影响因子：
17.7
作者：
Bearden, CE;Jawad, AF;Simon, TJ
通讯作者：
Simon, TJ
影响因子：
3.3
作者：
Harsing, LG;Zigmond, MJ
通讯作者：
Zigmond, MJ
DOI：
10.1073/pnas.0704848104
发表时间：
2007-09-11
影响因子：
11.1
作者：
Kargieman, Lucila;Santana, Noemi;Artigas, Francesc
通讯作者：
Artigas, Francesc
影响因子：
7.6
作者：
LAHTI, AC;KOFFEL, B;TAMMINGA, CA
通讯作者：
TAMMINGA, CA
影响因子：
56.9
作者：
Lois, C;Hong, EJ;Baltimore, D
通讯作者：
Baltimore, D