内质网Ca2+通道调节蛋白FKBP12.6在条件性恐惧记忆中的作用及机制研究

Normal fear memory can make us avoid danger, however, excessive fear memory is harmful to us, the mechanisms underlying fear memory are still unclear. Fkbp12.6, a subunit of RyR2 which is a calcium channel of endoplasmic reticulum, plays an important role in regulation intracellular Ca2+ signaling, and regulates spatial memory in hippocampus. FKBP12.6 and RyR2 are expressed in amygdala, a key regulatory region of fear memory. However, whether it could modulate fear memory is still unknown. We found that cued fear memory is impaired in FKBP12.6 knockout mice, indicating FKBP12.6 might play a role in cued fear memory. Thus, it is interesting for us to further study the role of FKBP12.6 in cued fear memory and the underlying mechanisms. First, we will investigate whether FKBP12.6 regulates cued fear memory in amygdala, and study the role of FKBP12.6 in memory acquisition, consolidation and expression. Second, the effects of FKBP12.6 on amygdala LTP induction and neurotransmitter release will be detected. Finally, the role of FKBP12.6 in amygdala neuron morphology will be investigated.This project will, for the first time, indicate the role of FKBP12.6 in cued fear memory and the underlying mechanisms, and might provide novel target for the regulation of fear memory.

正常恐惧记忆使我们躲避伤害，过度恐惧对我们造成困扰，目前恐惧记忆的机制仍不清楚。FKBP12.6是内质网RyR2钙离子通道的亚基，是胞内钙离子信号的重要调节蛋白，在海马参与空间记忆的调控。FKBP12.6及RyR2在调控恐惧记忆的关键脑区杏仁核均有较高表达，而其对恐惧记忆的影响仍然未知。申请人前期结果发现FKBP12.6敲除小鼠的条件性恐惧记忆显著受损，故本项目将进一步研究其对恐惧记忆的作用及机制。首先，在条件性恐惧模型中研究FKBP12.6对记忆调控与杏仁核的关联，以及对记忆获取、巩固、读出阶段的调控；其次，研究其对杏仁核神经元LTP及神经递质释放的影响；最后，研究其对杏仁核神经元形态的影响。本项目将首次明确FKBP12.6在条件性恐惧记忆中的作用、作用位点、作用时间，以及对杏仁核神经元功能与结构的影响，为恐惧记忆的调控提供理论依据和新的药物靶点。

Calstabin2，也被称为FK506结合蛋白12.6 (FKBP12.6)，是细胞内钙通道ryanodine受体亚型2 (RyR2)大分子复合物的一个亚基。我们之前的研究及他人的报道表明：calstabin2在海马中参与空间记忆的调节。Calstabin2和RyR2广泛分布在大脑中，包括杏仁核，而杏仁核是参与调节恐惧等情绪的关键脑区；但是calstabin2在恐惧记忆中的作用所知甚少。在条件恐惧模型中，我们发现calstabin2的基因缺失会削弱长期记忆。在外侧杏仁核(LA)中干扰calstabin2的表达也会导致条件恐惧记忆表达的降低。此外，calstabin2基因敲除的小鼠皮层和丘脑至外侧杏仁核的长期程增强效应(LTP)显著降低。综上所述，我们的结果表明外侧杏仁核的calstabin2在恐惧记忆的调节中起着关键作用。