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 PKMz and PKCz. In the genetic absence of Pin1, hippocampal L-LTP is increased as are the levels of PKMz and PKCz. PKMz and PKCz 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 PKMz and PKCz . 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 PKMz in regulating Pin1 and 2) further characterize PKMz function by identifying its downstream targets through chemical-genetics.
The successful completion of this project will increase our understanding of how chemical information relayed from adjacent neurons is converted into permanent, structural changes. This process is required for learning and thus is fundamental for understanding brain development, information processing and memory.
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| Westmark, Cara J; Westmark, Pamela R; Malter, James S (2009) MPEP reduces seizure severity in Fmr-1 KO mice over expressing human Abeta. Int J Clin Exp Pathol 3:56-68 |
