Region-specific inhibition of 14-3-3 proteins induces psychomotor behaviors in mice
Region-specific inhibition of 14-3-3 proteins induces psychomotor behaviors in mice
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DOI：
10.1038/s41537-018-0069-1
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发表时间：
2019-01-14
影响因子：
5.4
通讯作者：
Zhou, Yi
中科院分区：
文献类型：
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作者：
Graham, Kourtney;Zhang, Jiajing;Zhou, Yi
14-3-3蛋白家族在基因上与包括精神分裂症在内的几种精神疾病有关。我们的14-3-3功能敲除（FKO）小鼠，以及其他14-3-3敲除模型，已被证明表现出与精神分裂症相关的行为内表型。虽然特定的前脑区域，如前额皮质（PFC）和海马体（HP），与精神分裂症的病理生理有关，但这些大脑区域在自上而下控制特定精神分裂症相关行为中的作用尚未得到研究。本研究采用腺相关病毒（AAV）递送shRNA敲低14-3-3-inhibitor转基因基因的表达，从而选择性地恢复14-3-3- FKO小鼠前脑的功能。我们发现，在PFC和HP中注射AAV-shRNA对减弱14-3-3- FKO小鼠的精神运动活性是必要的。此外，我们发现，通过向PFC和HP传递表达14-3-3抑制剂的AAV，对14-3-3的急性抑制可以引发精神运动性躁动。有趣的是，当分别评估两个大脑区域时，我们确定aav介导的14-3-3抑制剂在HP内特异性表达足以诱导多种行为缺陷，包括多动症、联想学习和记忆受损以及感觉运动门控减少。此外，我们发现突触后NMDA受体水平受到急性14-3-3操作的调节。综上所述，本研究的发现直接将特定前脑区域的14-3-3抑制与某些精神分裂症相关的内表型联系起来。
The 14-3-3 family of proteins is genetically linked to several psychiatric disorders, including schizophrenia. Our 14-3-3 functional knockout (FKO) mice, as well as other 14-3-3 knockout models, have been shown to exhibit behavioral endophenotypes related to schizophrenia. While specific forebrain regions, such as the prefrontal cortex (PFC) and hippocampus (HP), have been implicated in schizophrenic pathophysiology, the role of these brain regions in the top-down control of specific schizophrenia-associated behaviors has not been examined. Here, we used an adeno-associated virus (AAV) delivered shRNA to knock down the expression of the 14-3-3-inhibitor transgene, thus selectively restoring the function of 14-3-3 in the forebrain of the 14-3-3 FKO mice, we found that injection of the AAV-shRNA into both the PFC and the HP is necessary to attenuate psychomotor activity of the 14-3-3 FKO mice. Furthermore, we found that acute inhibition of 14-3-3, through the delivery of an AAV expressing the 14-3-3 inhibitor to both the PFC and HP, can trigger psychomotor agitation. Interestingly, when assessing the two brain regions separately, we determined that AAV-mediated expression of the 14-3-3 inhibitor specifically within the HP alone is sufficient to induce several behavioral deficits including hyperactivity, impaired associative learning and memory, and reduced sensorimotor gating. In addition, we show that post-synaptic NMDA receptor levels are regulated by acute 14-3-3 manipulations. Taken together, findings from this study directly link 14-3-3 inhibition in specific forebrain regions to certain schizophrenia-associated endophenotypes.