Spastin转运AMPA受体GluA1亚基介导树突棘可塑性的机制

我们已经证实，促进树突形成分支的同时，spastin依赖其AAA结构域释放的微管动力募集树突棘AMPA受体。进一步研究发现，spastin与AMPA受体GluA1亚基C末端直接结合，并共存于树突；如果过表达spastin则促进GluA1膜表达；说明spastin能够作为结合蛋白转运GluA1上膜。那么，spastin通过什么途径把GluA1转运至树突棘？机制是什么？如何易化突触传递？为此，我们提出spastin通过转运GluA1亚基介导树突棘可塑性的假说。本项目拟分析：①spastin介导GluA1转运的部位；②促进GluA1转运的途径和机制；③如何通过GluA1转运调控树突棘可塑性和突触传递；旨在解析spastin转运AMPA受体GluA1亚基上膜的新功能，阐明spastin调控树突棘可塑性以及突触传递的机制，为明确spastin通过GluA1转运参与认知功能障碍发生提出切实的科学依据。

Most excitatory transmission in the brain is mediated by AMPA receptors. Therefore, the presence of these receptors at synapses has to be carefully regulated in order to ensure correct neuronal communication. Interestingly, AMPA receptors are not static components of synapses. On the contrary, they are continuously being delivered and removed in and out of synapses in response to neuronal activity. This dynamic behavior of AMPA receptors is an important mechanism to modify synaptic strength during brain development and also during experience-dependent plasticity. AMPA receptor trafficking involves an intricate network of protein-protein interactions that start with the biosynthesis of the receptors, continues with their transport along dendrites, and ends with their local insertion and removal from synapses. Our preliminary results showed that short microtubules, produced by the spastin-severing of long microtubules, are the ones that undergo the dynamic of microtubule crucial for dendritic growth. However, overexpression of spastin increased the number of dendritic branches, and interestingly, spastin promoted AMPA receptor assembly in cell membrane as well. Is it spastin to take part in AMPA receptors trafficking? Further, our results revealed that spastin can interact with the C-terminal region of GluA1 subunit of AMPA receptors and increased the expression of GluA1 on the cell membrane. Why does spastin interact with AMPA receptor subunit GluA1? How does spastin take part in synaptic transmission and plasticity? Thus, we propose the hypothesis that spastin can transport GluA1 to dendritic spines along the microtubule to involve in synaptic plasticity. This project is aim to determine three questions by morphological, biological and physiological methods. The one is where the interaction region of spastin and GluA1 is. The other is the ways of spastin promoted GluA1 translocation to the membrane. The third is the relationship between spastin and synaptic plasticity and transmission. Answering these questions will elucidate the new function of spastin-mediated AMPA receptor trafficking, and will determine the new mechanism of spastin regulated synaptic transmission, and finally to provide evidences of spastin involving in cognitive deficits via the regulation of GluA1 trafficking.