神经元突触活性调控基因表达的机制研究

神经元接受外界刺激时，可以将信息传递到核内并调节基因表达，实现神经元的长时程调控。然而，神经元具有复杂的结构，那么，突触活性如何将信息通过树突传递到核内？目前的研究主要围绕着继发性钙波形成和某些蛋白的核转位展开，但不足以解释信号为什么在传递过程中没有发生衰减，以及不同传递途径时间和空间上的协作关系。内体接头蛋白APPL1在异源系统中被认为是信号内体的标记物。我们的前期研究显示，突触活性可以引起神经元APPL1的核转位；APPL1核转位依赖于clathrin介导的内化过程；如果利用多肽阻断APPL1入核，可以阻断突触活性引起的CREB磷酸化水平增高。因此我们提出假设，突触活性可能会引起某些受体的内化，进而在树突形成含内化受体/接头蛋白/信号分子的信号内体，将外界信息稳定地传递到细胞核，并调控基因表达及突触可塑性。这一假设的证明将对我们理解大脑感受外界刺激产生学习和记忆功能提供新的思路。

Local signaling events at synapses or axonal terminals are communicated to the nucleus to elicit transcriptional responses, and thereby translate information about the external environment into internal neuronal representations. Activity-dependent modification of gene expression is a powerful means by which the neurons build up long-term modification. However, the lengths of neuronal processes pose a significant challenge for such intracellular communications. Currently, calcium waves and translocation of key proteins to the nucleus are the two major pathways involved in signaling transduction along the dendrites. However, it is still unclear why the signals are transduced persistently and specifically. In the axon, signaling endosome containing internalized neurotropic receptor and downstream signaling molecular is another pathway that mediates the transduction of neurotropic signals along the axon. It is still unclear whether signaling endosome exists in the dendrites. Endosomal adaptor protein APPL1 is a marker for signaling endosome in the heterologous cells and is transduced into the nucleus after external stimulus such as stress. Here, we found that synaptic activity induced nuclear translocation of APPL1 in the excitatory neurons. In addition, a peptide against the nuclear localization sequence of APPL1 blocked synaptic activity-dependent nuclear translocation of APPL1, as well as the upregulation of CREB phosphorylation at Ser133 site in the nucleus. Furthermore, nuclear translocation of APPL1 was dependent on clathrin-mediated endocytosis. These data suggest that, in the dendrite, synaptic activity may also induce the formation of signaling endosome, which is responsible for the effective and long-term transduction of signals to the nucleus and modification of gene transcription. It will provide new information for us to understand the mechanisms how our brain is modified according to the external stimulus.