Pin1 in Synaptic Plasticity and Translation

突触可塑性和记忆的巩固需要突触分子组成的生化改变。巩固过程涉及多个过程，包括预先存在的树突mrna的局部翻译，并导致突触效能和新记忆存储的变化，这些变化持续数天至数年。虽然已经确定了一些记忆效应，但相对而言，人们对这些分子如何控制突触可塑性长期形式的诱导知之甚少。我们现在发现Pin1是一种顺式-反式肽基脯氨酸异构酶，对Ser-Pro或Thr-Pro肽键具有特异性，在突触可塑性中起关键作用。Pin1存在于树突和棘中，在基础条件下，抑制树突蛋白的合成。谷氨酸信号使Pin1失活，导致许多蛋白质的翻译增加，包括与可塑性相关的激酶PKM -耐受性和PKC -耐受性在Pin1基因缺失的情况下，海马L-LTP和PKM -耐受性和PKC -耐受性的水平增加。在谷氨酸信号传导和树突翻译后，PKM -和PKC -活性对于维持Pin1活性的抑制是必要的。这些数据表明谷氨酸能信号抑制Pin1，导致PKM和PKC的翻译。一旦产生，这些激酶就会通过抑制Pin1来部分支持正在进行的树突翻译。因此，我们的目标是确定1)PKM - 1在调节Pin1中的作用和2)通过化学遗传学鉴定其下游靶点进一步表征PKM - 1的功能。

Consolidation of synaptic plasticity and memory requires biochemical alterations in the molecular composition of the synapse. The process of consolidation involves multiple processes including local translation of preexisting, dendritic mRNAs and results in changes in synaptic efficacy and storage of new memories that persist from days to years. While a few of the effectors of memory have been identified, relatively little is understood about how these molecules govern the induction of long-term forms of synaptic plasticity. We now show that Pin1, a cis-trans peptidyl-prolyl isomerase with specificity for Ser-Pro or Thr-Pro peptide bonds, plays a key role in synaptic plasticity. Pin1 is present in dendrites and spines and under basal conditions, suppresses dendritic protein synthesis. Glutamate signaling inactivates Pin1, leading to increased translation of many proteins including the plasticity related kinases PKMand PKC In the genetic absence of Pin1, hippocampal L-LTP is increased as are the levels of PKMand PKC. PKMand PKCactivity were necessary to maintain the suppression of Pin1 activity after glutamate signaling as well as dendritic translation. These data suggest glutamatergic signaling inhibits Pin1 which leads to the translation of PKM and PKC. Once produced, these kinases then support on-going dendritic translation partially by suppressing Pin1. As such our aims are to determine 1) the role of PKMin regulating Pin1 and 2) further characterize PKM function by identifying its downstream targets through chemical-genetics.