Graham Kourtney, Zhang Jiajing, Qiao Haifa, Wu Yuying, Zhou Yi
Department of Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, FL, 32306, USA.
Key Laboratory of Acupuncture and Herbs, Shaanxi University of Chinese Medicine, Century Ave, Xianyang Shi, Shaanxi Province, 712046, China.
NPJ Schizophr. 2019 Jan 14;5(1):1. doi: 10.1038/s41537-018-0069-1.
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.
14-3-3蛋白家族在基因上与包括精神分裂症在内的多种精神疾病相关。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，如前额叶皮层（PFC）和海马体（HP），与精神分裂症的病理生理学有关，但这些脑区在对特定精神分裂症相关行为的自上而下控制中的作用尚未得到研究。在这里，我们使用腺相关病毒（AAV）递送的短发夹RNA（shRNA）来敲低14-3-3抑制剂转基因的表达，从而选择性地恢复14-3-3 FKO小鼠前脑中14-3-3的功能，我们发现将AAV-shRNA注射到PFC和HP中对于减弱14-3-3 FKO小鼠的精神运动活动是必要的。此外，我们发现通过向PFC和HP递送表达14-3-3抑制剂的AAV来急性抑制14-3-3，可以引发精神运动性激越。有趣的是，当分别评估这两个脑区时，我们确定仅在HP内特异性地通过AAV介导表达14-3-3抑制剂就足以诱发多种行为缺陷，包括多动、联想学习和记忆受损以及感觉运动门控降低。此外，我们表明急性14-3-3操作可调节突触后NMDA受体水平。综上所述，本研究的结果直接将特定前脑区域中的14-3-3抑制与某些精神分裂症相关的内表型联系起来。
