Post Transcriptional Mechanisms Of Neuronal Translational Control In Synaptic Plasticity

The dynamic complexity of synaptic function is matched by extensive multidimensional regulation of neuronal mRNA translation which is achieved by a number of post-transcriptional mechanisms. The first key aspect of this regulatory capacity is mRNA distal trafficking through RNA-binding proteins, which governs the transcriptomic composition of post-synaptic compartments. Small non-coding microRNA and associated machinery have the capacity to precisely coordinate neural gene networks in space and time by providing a flexible specificity dimension to translational regulation. This RNA-guided subcellular fine-tuning of protein synthesis is an exquisite mechanism used in neurons to exert control of synaptic properties. Emerging evidence also implicates brain-enriched long non-coding RNA and novel circular RNA in posttranscriptional regulation of gene expression through the modulation of both mRNA and miRNA functions, thereby exemplifying the complex nature of neuronal translation. Herein, we review current knowledge of these regulatory systems and analyse how these mechanisms of transcriptomic regulation may be linked together to achieve high-order spatiotemporal control of post-synaptic translation.

The NMDA receptor plays a critical role in the development of the central nervous system and in adult neuroplasticity, learning, and memory. Therefore, it is not surprising that this receptor has been widely studied. However, despite the importance of rhythms for the sustenance of life, this aspect of NMDAR function remains poorly studied. Written

A comprehensive, multidisciplinary review, Neural Plasticity and Memory: From Genes to Brain Imaging provides an in-depth, up-to-date analysis of the study of the neurobiology of memory. Leading specialists share their scientific experience in the field, covering a wide range of topics where molecular, genetic, behavioral, and brain imaging techniq

The genetic, molecular, and cellular mechanisms of neural development are essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information, but there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. The Comprehensive Developmental Neuroscience series is designed to fill this gap, offering the most thorough coverage of this field on the market today and addressing all aspects of how the nervous system and its components develop. Particular attention is paid to the effects of abnormal development and on new psychiatric/neurological treatments being developed based on our increased understanding of developmental mechanisms. Each volume in the series consists of review style articles that average 15-20pp and feature numerous illustrations and full references. Volume 1 offers 48 high level articles devoted mainly to patterning and cell type specification in the developing central and peripheral nervous systems. Series offers 144 articles for 2904 full color pages addressing ways in which the nervous system and its components develop Features leading experts in various subfields as Section Editors and article Authors All articles peer reviewed by Section Editors to ensure accuracy, thoroughness, and scholarship Volume 1 sections include coverage of mechanisms which: control regional specification, regulate proliferation of neuronal progenitors and control differentiation and survival of specific neuronal subtypes, and controlling development of non-neural cells

Precise control of protein translation in neurons, particularly translation occurring in dendrites near synaptic sites, is critical for the proper regulation of synaptic strength. The most direct way to affect the strength of glutamatergic synapses is to alter the abundance of AMPA-type glutamate receptors (AMPARs). Here I demonstrate the critical role that two separate translational regulators play in controlling the translation of the AMPAR subunit GluR1, both under steady-state conditions and during synaptic plasticity. Homeostatic synaptic plasticity adjusts the strength of synapses during global changes in neural activity, thereby stabilizing the overall activity of neural networks. Suppression of synaptic activity increases synaptic strength by inducing synthesis of retinoic acid (RA), which activates postsynaptic synthesis and insertion of AMPARs. Here, I show that the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein that regulates dendritic protein synthesis, is essential for increases in synaptic strength induced by RA or by blockade of neural activity in the mouse hippocampus. Although activity-dependent RA synthesis is maintained in Fmr1 knockout neurons, RA-dependent dendritic translation of GluR1-type AMPARs is impaired. Intriguingly, FMRP is only required for the form of homeostatic plasticity which is dependent on both RA signaling and local protein synthesis. Expression of FMRP in knockout neurons reduced the total, surface, and synaptic levels of AMPARs, implying a role for FMRP in regulating AMPAR abundance. Critically, postsynaptic expression in knockout neurons of wild-type FMRP, but not two different mutant forms of the protein, was able to fully restore synaptic scaling. microRNAs (miRNAs) are small RNA molecules which bind to the untranslated regions of mRNAs and inhibit translation. Using a bioinformatics approach, I identified a pair of miRNAs, miR-96 and miR-182, which bind specifically to a known sequence in the GluR1 mRNA and prevent its translation. When overexpressed, these miRNAs reduce total and extrasynaptic levels of GluR1 protein in neurons, and prevent the induction of homeostatic plasticity by activity blockade. Both miR-96 and miR-182 are expressed in cortex throughout postnatal development, although we were unable to detect activity-dependent changes in the abundance of either miRNA. Attempted knockdown of both miRNAs revealed no significant effect on the abundance of GluR1 or the ability of neurons to undergo homeostatic plasticity. Taken together, these data offer significant insight into the regulation of local translation of glutamate receptors at the synapse, particularly during specific forms of synaptic plasticity. These results also suggest that some of the symptoms of Fragile-X syndrome may be attributed to defects in the induction of homeostatic plasticity.

Since the 1996 publication of Translational Control, there has been fresh interest in protein synthesis and recognition of the key role of translation control mechanisms in regulating gene expression. This new monograph updates and expands the scope of the earlier book but it also takes a fresh look at the field. In a new format, the first eight chapters provide broad overviews, while each of the additional twenty-eight has a focus on a research topic of more specific interest. The result is a thoroughly up-to-date account of initiation, elongation, and termination of translation, control mechanisms in development in response to extracellular stimuli, and the effects on the translation machinery of virus infection and disease. This book is essential reading for students entering the field and an invaluable resource for investigators of gene expression and its control.

Neurons are highly-polarized cells with processes that span great distances and many independent subcompartments. Despite their challenging morphology, neurons are able to respond to external stimuli in a local or cell-wide manner. They are also able to form stable connections with other neurons, while remaining plastic and adaptable to change. To meet these demands, neurons use complex, post-transcriptional mechanisms to regulate gene expression. Two approaches are taken in this dissertation to study post-transcriptional gene regulation in neurons. First, a cell biological approach was used to study a specific interaction between the microRNA, miR-124, and GluA2 mRNA in dissociated hippocampal neurons. The subcellular localization pattern of miR-124 and GluA2 mRNA was determined by extracting RNA from synaptosome fractions and by direct visualization with fluorescence in situ hybridization. The effect of miR-124 overexpression on endogenous GluA2 protein was determined by immunoblotting and again by direct visualization with quantitative immunocytochemistry. These experiments reveal that miR-124 is dendritically-localized while GluA2 mRNA is somatically-restricted. Both RNAs are present in the cell body, where they interact to downregulate GluA2 proteins in the soma by ~30 %. Synaptic GluA2 protein was not affected by this manipulation, suggesting that post-translational regulatory mechanisms (e.g. trafficking) are in place to maintain appropriate concentrations of GluA2 at the synapse. Second, a high-throughput sequencing approach was taken to identify general mechanisms of gene regulation during chemical long-term potentiation (chemLTP) in acute hippocampal slices, as well as to screen for interesting candidates for further investigation. RNA was extracted from chemLTP-treated and control slices, and changes in steady-state RNA levels were determined. This study is ongoing but so far, preliminary results suggest that non-neuronal cells may play an important role in the strengthening of neuronal connections. Future analysis will focus on 3' untranslated regions, which determine the post-transcriptional fate of genes. The two approaches provide different levels of information on the regulation of gene expression in neurons and yield unexpected findings. Together, they illustrate the complexity of regulatory mechanisms in neurons, and that there is much we have left to understand.

MRNA localization and regulated translation allow individual neurons to locally regulate the proteome of each of their many subcellular compartments. To investigate the spatial regulation of gene expression during synaptic plasticity, we used a translational reporter system to demonstrate synapse- and stimulus-specific translation during long-term facilitation of Aplysia sensory-motor synapse. These studies revealed a role for a retrograde signal from the postsynaptic motor neuron in regulating translation in the presynaptic sensory neuron. Additional studies with the translational reporter demonstrated that distinct cis-acting localization elements were involved in targeting mRNA to distal neurites and to synapses. Our studies identified a 66 nucleotide long stem loop structure that directs mRNAs to synapses. In the final part of my thesis research, I addressed the question of whether and how synaptogenic signals direct mRNA targeting and spatially regulate gene expression during synapse formation. I cultured a bifurcated Aplysia sensory neuron contacting a nontarget motor neuron, with which it did not form chemical synapses, and a target motor neuron, with which it formed glutamatergic synapses, and imaged RNA and protein localization. I find that RNAs and translational machinery are delivered throughout the neuron, but that translation is enriched at sites of synaptic contact. Investigation of the molecular mechanisms that promote local translation revealed a role for netrin1-DCC signaling. Together, my research indicates that the spatial regulation of gene expression during synapse formation and during synaptic plasticity is mediated at the level of translation. This mechanism maximizes neuronal plasticity by rendering each compartment capable of locally changing its proteome in response to local cues.

Nerve cells form thousands of contact points, the synapses, to communicate information with other neurons and target cells. Synapses are sites for changes in brain function through modification of synaptic transmission termed synaptic plasticity. The study of synaptic plasticity has flourished over the years with the advancement of technical breakthroughs and is a timely scientific endeavor today just like it was several decades ago. This book contributes to our understanding of synaptic plasticity at the molecular, biochemical, and cellular systems and behavioral level and informs the reader about its clinical relevance. The book contains ten chapters in three sections: (1) "Mechanisms of Synaptic Plasticity," (2) "Neural Plasticity," and (3) "Plasticity and Neurological Diseases." The book provides detailed and current reviews in these different areas written by experts in their respective fields. The mechanisms of synaptic plasticity and its relation to neurological diseases are featured prominently as a recurring theme throughout most chapters. This book will be most useful for neuroscientists and other scientists alike and will contribute to the training of current and future students who find the plastic nervous system as fascinating as many generations before them.