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Balancing Synaptic and Homeostatic Plasticity through Local Translation of Receptors and Ion Channels

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Local protein synthesis can remodel a synapse rapidly, independent of new transcription or protein trafficking. Although its requirement in long-term forms of synaptic plasticity is established, little is known about the role of local translation in facilitating homeostatic plasticity. Here, we focus on how ...

Local protein synthesis can remodel a synapse rapidly, independent of new transcription or protein trafficking. Although its requirement in long-term forms of synaptic plasticity is established, little is known about the role of local translation in facilitating homeostatic plasticity. Here, we focus on how local translation of receptors and ion channels foster Hebbian and homeostatic plasticities, as an imbalance between these plasticities can influence memory loss, neurodegeneration, epilepsy, autism, depression and addiction.
Precise activation and inactivation of signaling pathways that initiate translation or relieve translational repression are vital to normal neuronal signaling. When these pathways are aberrantly active or inactive they lead to diseases such as epilepsy, Tuberous Sclerosis Complex (TSC), Fragile X Syndrome (FXS), Alzheimer’s disease, Parkinson’s disease, Rhett’s syndrome, depression, and addiction. The contribution of local protein synthesis to these disease states is beginning to emerge.
A reoccurring theme among development and neurodegenerative diseases is that unregulated local translation may push the neuron into a hyperexcitable state, favoring synaptic over homeostatic plasticity. The signaling pathways of the mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase (ERK) promote local protein synthesis and are dysregulated in epilepsy, Autism Spectrum Disorders and addiction. This may be, in part, due to the excessive local translation of plasticity related genes, such as Arc and CaMKIIα, and sustained repression of potassium channel mRNAs.
Reactivation of stalled translation through the eukaryotic elongation factor 2 (eEF2) is gaining attention for mediating mGluR-dependent LTD and relief of depression by rapid antidepressants. Blocking NMDAR activity or activating mGluRs dephosphorylates the eEF2 kinase, the kinase that inhibits EF2, allowing translation of stalled transcripts. Release of stalled polyribosomes to increase protein synthesis of specific transcripts is likely to be a critical cellular mechanism to support many forms of plasticity.
How signaling pathways control the activities of RNA-binding factors is a topic of great interest and potential therapeutic relevance. RNA-binding factors include RNA-binding proteins, microRNAs, and long-coding mRNAs. During normal plasticity these factors may be limited and compete for specific targets. During disease states the abundance of these factors may shift to tip the scales toward over-active translation and repression of plasticity related mRNAs and homeostatic mRNAs, respectively. The importance of dynamic regulation of RNA-binding factors in normal and diseased neurons will prove to be important to regulate gene expression of proteins with coordinated function.
In this Research Topic we wish to summarize how local protein synthesis is required for synaptic and homeostatic plasticity yielding insight into how site-specific translation can contribute to learning and memory. Furthermore, we wish to explore the issue of how regulation of local synthesis is disrupted in developmental and neurological diseases. The presentation of original work and perspectives regarding the future relevance of site-specific neuronal protein synthesis to neuronal signaling and rational drug design is encouraged.


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