PTSD的产生与遗忘机制失调有关。突触长时程抑制（LTD）在遗忘过程中发挥重要的作用。以往研究表明LTD的晚期（L-LTD）需要基因转录和蛋白降解的参与，而申请人前期预实验结果发现LTD可以诱导CRTC1入核并结合CREB调控蛋白降解（如自噬）相关基因的转录，提示该信号通路可能参与神经元活动和基因转录及蛋白降解的偶联，但具体作用机制及其是否与L-LTD及遗忘相关目前还不清楚。针对这一关键科学问题，项目将利用原代培养神经元和模式小鼠，通过ChIP-seq、免疫组化、电生理和行为学等方法深入研究CRTC1-CREB介导的兴奋性基因转录的作用机制，从而在分子、细胞和在体动物水平系统阐明其与AMPAR降解，L-LTD和遗忘的关系。该研究是一项全新的研究，其完成有利于阐明L-LTD的分子机制这一关键科学问题，并为PTSD等疾病的药物开发提供新的靶点和科学依据。

PTSD is related with forgetting dysfunction. Synaptic long-term depression is crucial in forgetting. Previous research has shown that late phase LTD (L-LTD) involved gene transcription and protein degradation. The preliminary experiment of the applicant showed that CRTC1 can translocate into the nucleus and bind with CREB to activate protein degradation related gene expression, such as autophagy related genes, indicating that this signal pathway may couple the neuronal activity with gene transcription. But, both the specific mechanism of this process and how does it associate with L-LTD or forgetting remain elusive. Focusing on this key scientific problem, this project will use the cultured primary neurons and model mice to study how CRTC1-CREB mediates the activity-dependent gene transcription through ChIP-seq, immune-histochemical, electro-physiological and animal behavior methods. Experiments will be designed from molecular, cellular and animal level, in order to clarify its relationship with AMPAR degradation, L-LTD and forgetting. This is a brand new study, and its completion will help illuminate the molecular mechanism of L-LTD, and provide new targets and scientific basis for drug development of diseases related to forgetting disorder, such as PTSD.