RNA结合蛋白CPEB3介导的GluA1亚单位在恐惧消退中突触可塑性的作用

恐惧消退是通过形成新的抑制性学习来拮抗最初的恐惧记忆，消退失败将导致创伤后应激障碍症等多种精神疾病的发生。新近研究证实恐惧消退中杏仁核的GluA1亚单位效能及诱发的突触反应性明显增高，能否通过调控GluA1亚单位的效能来探寻促进恐惧消退的方法？但目前如何调控GluA1亚单位的效能活性尚不明确。CPEB3是影响神经可塑性和学习记忆的RNA结合蛋白，我们前期研究显示CPEB3在突触近端呈梯度增加，推测CPEB3介入调控GluA1亚单位的效能活性，从而参与恐惧消退过程。据此，本项目利用杏仁核特异性CPEB3基因敲除鼠结合lenti-CPEB3靶向修复从正反两面阐明CPEB3介导的GluA1亚单位效能活性以及所诱发的突触可塑性调节；运用光遗传学技术观察“恐惧消退神经元”的突触传递；采用在体光纤追踪恐惧消退行为中的突触可塑性调节；以阐明RNA结合蛋白CPEB3介导的GluA亚单位在恐惧消退中的作用。

Fear extinction involves creating a conditioned response that counters the conditioned fear response. Failure of extinction of fear responses in Posttraumatic Stress Disorder (PTSD). Nowadays, a major mechanism contributing to fear extinction involves alterations in the number of GluA1 subunit expression and increasingly synaptic plasticity in the amygdala. Therefore, could we find the pathway that the regulate the fear extinction through the activity of GluA1 subunit? However, a longstanding question is how the spatial organization of synaptic receptors subunit GluA1 is achieved. CPEB, an indispensable RNA binding protein in dendrite, maintain synaptic plasticity, synaptic growth, and memory storage. We founded graded dendritic depolarizations elevated CPEB3 protein at proximal dendrites, where we suggest that RNA binding protein CPEB3 regulate subunit GluA1 at synapse, modulating to the fear extinction. Base on that, we hypothesized that CPEB3 might contribute to mediate fear extinction through regulating the GluA1 subunit. In this study, we will knock out CPEB3 in the amygdala in mice, combined with lenti-CPEB3 to detect the CPEB3 function on the GluA1 subunit from the negative and positive sides, to observe the GluA1 expression in synaptic plasticity, to record neuronal activity in amygdala following fear extinction through optogenetic technique, to build fear conditioning model and track fear extinction neuron synapse in the behavioral assessment through in vivo fiber phytotomy. These findings on CPEB3-reglated GluA1 subunit would prompt us to clarify the mechanism of fear extinction and may underlie the pathophysiology and cure fear extinction.