Chen Y-H, Lan Y-J, Zhang S-R, Li W-P, Luo Z-Y, Lin S, Zhuang J-P, Li X-W, Li S-J, Yang J-M, Gao T-M
State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
Transl Psychiatry. 2017 Jul 4;7(7):e1168. doi: 10.1038/tp.2017.139.
Many psychiatric diseases such as post-traumatic stress disorder (PTSD) are characterized by abnormal processing of emotional stimuli particularly fear. The medial prefrontal cortex (mPFC) is critically involved in fear expression. However, the molecular mechanisms underlying this process are largely unknown. Neuregulin-1 (NRG1) reportedly regulates pyramidal neuronal activity via ErbB4 receptors, which are abundant in parvalbumin (PV)-expressing interneurons in the PFC. In this study, we aimed to determine how NRG1/ErbB4 signaling in the mPFC modulates fear expression and found that tone-cued fear conditioning increased NRG1 expression in the mPFC. Tone-cued fear conditioning was inhibited following neutralization of endogenous NRG1 and specific inhibition or genetic ablation of ErbB4 in the prelimbic (PL) cortex but not in the infralimbic cortex. Furthermore, ErbB4 deletion specifically in PV neurons impaired tone-cued fear conditioning. Notably, overexpression of ErbB4 in the PL cortex is sufficient to reverse impaired fear conditioning in PV-Cre;ErbB4 mice. Together, these findings identify a previously unknown signaling pathway in the PL cortex that regulates fear expression. As both NRG1 and ErbB4 are risk genes for schizophrenia, our study may shed new light on the pathophysiology of this disorder and help to improve treatments for psychiatric disorders such as PTSD.
许多精神疾病，如创伤后应激障碍（PTSD），其特征在于对情绪刺激尤其是恐惧的异常处理。内侧前额叶皮质（mPFC）在恐惧表达中起关键作用。然而，这一过程背后的分子机制在很大程度上尚不清楚。据报道，神经调节蛋白-1（NRG1）通过ErbB4受体调节锥体神经元活动，这些受体在PFC中表达小白蛋白（PV）的中间神经元中大量存在。在本研究中，我们旨在确定mPFC中的NRG1/ErbB4信号如何调节恐惧表达，并发现音调提示恐惧条件反射增加了mPFC中NRG1的表达。在内源性NRG1中和以及前边缘（PL）皮质中ErbB4的特异性抑制或基因敲除后，音调提示恐惧条件反射受到抑制，但在边缘下皮质中未受抑制。此外，仅在PV神经元中删除ErbB4会损害音调提示恐惧条件反射。值得注意的是，在PL皮质中过表达ErbB4足以逆转PV-Cre;ErbB4小鼠中受损的恐惧条件反射。总之，这些发现确定了PL皮质中一条以前未知的调节恐惧表达的信号通路。由于NRG1和ErbB4都是精神分裂症的风险基因，我们的研究可能为这种疾病的病理生理学提供新的线索，并有助于改善对PTSD等精神疾病的治疗。
