DendriticmRNAs: Localization and translational regulation during synaptic plasticity.

摘要

Studies over the past 20 years have highlighted that protein synthesis can not only happened in the neuronal cell body, but also in dendrites where the synapses form. Local protein synthesis in dendrites endows the synapses the ability to autonomously regulate the strength of synaptic efficacy, which is of particular relevance in neurons because of their complex cellular architecture and synaptic input. Increasing evidence show that activity-dependent synaptic plasticity, like LTP and LTD require local synthesis of proteins within dendrites. In situ hybridization evidence suggests that only a small number of mRNAs are localized in dendrites and the vast majority of mRNAs that have been evaluated are localized exclusively in neuronal cell bodies. Some mRNAs are constitutively localized in dendrites, while some can be regulated by patterned synaptic activity.; Identifying novel dendritic mRNAs and determining how their distribution and translation is regulated is a high priority for the study of local protein synthesis. In my thesis work, First, I demonstrate that EF1alpha mRNA is present in dendrites of mammalian neurons in vivo. Neither the levels nor the distribution of the mRNA is altered by prolonged periods of intense synaptic activity that induce LTP, indicating that mRNA distribution in dendrites is relatively stable. Also, induction of LTP does not lead to new EF1alpha protein synthesis in dendrites, whereas pharmacological activation of metabotropic glutamate receptors (mGluRs), triggers dramatic increases in EF1alpha synthesis within dendrites. Second, I show that rapid polymerization of actin, ERK phosphorylation, and IEG induction following high frequency stimulation of the perforant path in vivo are all mediated by NMDA receptor activation. Local application of a Rho-kinase (ROCK) inhibitor blocks actin polymerization, ERK phosphorylation, and Arc mRNA and protein targeting to the activated dendritic lamina. Local application of Latrunculin B, which inhibits actin polymerization, blocked ERK1/2 phosphorylation, and the induction of IEG expression, and also blocked the targeting of Arc mRNA to synaptic sites induced by HFS. Our results indicate that the reorganization of the actin cytoskeletal network plays critical roles in signaling pathway activation and targeting newly-synthesized Arc mRNA and protein to activated synaptic sites on dendrites.