Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice
Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice
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DOI：
10.1371/journal.pone.0007461
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发表时间：
2009-10-14
期刊：
影响因子：
3.7
通讯作者：
Hara, Hideaki
中科院分区：
文献类型：
--
作者：
Oyagi, Atsushi;Oida, Yasuhisa;Hara, Hideaki
最近，神经营养因子和细胞因子已被证明与精神疾病，如精神分裂症，双相情感障碍和抑郁症。肝素结合表皮生长因子样生长因子（HB-EGF）是EGF家族的成员，作为一种神经营养分子，在大脑中发挥重要作用。我们产生了小鼠，其中HB-EGF活性被破坏，特别是在腹侧前脑。这些基因敲除小鼠表现出（a）与精神疾病中描述的行为异常相似的行为异常，其通过典型或非典型抗精神病药物得到改善，（B）脑中多巴胺和5-羟色胺水平改变，（c）前额叶皮层神经元的棘密度降低，（d）N-甲基-D-天冬氨酸（NMDA）受体的NR 1亚基和突触后蛋白-95（PSD-95）的蛋白水平的降低，（e）EGF受体的降低，和钙/钙调蛋白依赖性蛋白激酶II（CaMK II）信号级联。这些结果表明，影响HB-EGF信号转导的改变可能是精神疾病的一个促成因素。
Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.