Dendritic mRNA Translation Research Articles

MiR-329– and miR-495–mediated Prr7 down-regulation is required for homeostatic synaptic depression in rat hippocampal neurons

Homeostatic synaptic depression (HSD) in excitatory neurons is a cell-autonomous mechanism which protects excitatory neurons from over-excitation as a consequence of chronic increases in network activity. In this process, excitatory synapses are weakened and eventually eliminated, as evidenced by a reduction in synaptic AMPA receptor expression and dendritic spine loss. Originally considered a global, cell-wide mechanism, local forms of regulation, such as the local control of mRNA translation in dendrites, are being increasingly recognized in HSD. Yet, identification of excitatory proteins whose local regulation is required for HSD is still limited. Here, we show that proline-rich protein 7/transmembrane adapter protein 3 (Prr7) down-regulation in dendrites of rat hippocampal neurons is necessary for HSD induced by chronic increase in network activity resulting from a blockade of inhibitory synaptic transmission by picrotoxin (PTX). We further identify two activity-regulated miRNAs, miR-329-3p and miR-495-3p, which inhibit Prr7 mRNA translation and are required for HSD. Moreover, we found that Prr7 knockdown reduces expression of the synaptic scaffolding protein SPAR, which is rescued by pharmacological inhibition of CDK5, indicating a role of Prr7 protein in the maintenance of excitatory synapses via protection of SPAR from degradation. Together, our findings highlight a novel HSD mechanism in which chronic activity leads to miR-329- and miR-495-mediated Prr7 reduction upstream of the CDK5-SPAR pathway.

Alterations in dendritic GABAB receptor expression in an Alzheimer’s disease mouse model

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory deficits and cognitive decline. Major hallmarks that occur during early stages of disease progression include amyloid beta plaque, neurofibrillary tangles, and synaptic loss. The mechanisms that particularly govern synaptic loss, however, remain under investigation. Local, dendritic mRNA translation is critical in maintaining proper synaptic architecture as well as engagement with presynaptic terminals. A master regulator of this process is controlled by mammalian target of rapamycin complex 1 (mTORC1), whose activity has shown to be significantly increased in AD patients as well as respective animal models. Increases in mTORC1 activity have consequently shown to upregulate the translation of various downstream synaptic proteins, one of those being GABAB receptors (Niere, 2016). Metabotropic, GABAB receptors are critical in maintaining slow, sustained inhibition throughout the central nervous system. However, their significance towards synaptic function is understudied in the context of AD.MethodsOur study utilized immunocytochemistry and microscopy to determine changes in GABAB1 receptor subunit expression in hippocampal dissociated neurons. Additionally, APP/PS1 transgenic mice were used as our model for AD.ResultsImmunocytochemical results indicate approximately a 22% increase in dendritic GABAB1 subunit expression in AD mice as compared to wildtypes (p<0.01).ConclusionsThe data indicates increases in GABAB1 receptor subunits in AD while highlighting a potential avenue in which transsynaptic signaling is disrupted in early stages of AD.

On the dynamical aspects of local translation at the activated synapse

BackgroundThe key role in the dynamic regulation of synaptic protein turnover belongs to the Fragile X Mental Retardation Protein, which regulates the efficiency of dendritic mRNA translation in response to stimulation of metabotropic glutamate receptors at excitatory synapses of the hippocampal pyramidal cells. Its activity is regulated via positive and negative regulatory loops that function in different time ranges, which is an absolute factor for the formation of chaotic regimes that lead to disrupted proteome stability. The indicated condition may cause a number of neuropsychiatric diseases, including autism and epilepsy. The present study is devoted to a theoretical analysis of the local translation system dynamic properties and identification of parameters affecting the chaotic potential of the system.ResultsA mathematical model that describes the maintenance of a specific pool of active receptors on the postsynaptic membrane via two mechanisms – de novo synthesis of receptor proteins and restoration of protein function during the recycling process – has been developed. Analysis of the model revealed that an increase in the values of the parameters describing the impact of protein recycling on the maintenance of a pool of active receptors in the membrane, duration of the signal transduction via the mammalian target of rapamycin pathway, influence of receptors on the translation activation, as well as reduction of the rate of synthesis and integration of de novo synthesized proteins into the postsynaptic membrane – contribute to the reduced complexity of the local translation system dynamic state. Formation of these patterns significantly depends on the complexity and non-linearity of the mechanisms of exposure of de novo synthesized receptors to the postsynaptic membrane, the correct evaluation of which is currently problematic.ConclusionsThe model predicts that an increase of “receptor recycling” and reduction of the rate of synthesis and integration of de novo synthesized proteins into the postsynaptic membrane contribute to the reduced complexity of the local translation system dynamic state. Herewith, stable stationary states occur much less frequently than cyclic states. It is possible that cyclical nature of functioning of the local translation system is its “normal” dynamic state.

Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition.

There has been much recent progress in understanding of the mechanism of ketamine's rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses. This drug-on phase lasts for approximately 2h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca2+ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine.

Sam68 Enables Metabotropic Glutamate Receptor-Dependent LTD in Distal Dendritic Regions of CA1 Hippocampal Neurons

SUMMARYThe transport and translation of dendritic mRNAs by RNA-binding proteins (RBPs) allows for spatially restricted gene expression in neuronal processes. Although local translation in neuronal dendrites is now well documented, there is little evidence for corresponding effects on local synaptic function. Here, we report that the RBP Sam68 promotes the localization and translation of Arc mRNA preferentially in distal dendrites of rodent hippocampal CA1 pyramidal neurons. Consistent with Arc function in translation-dependent synaptic plasticity, we find that Sam68 knockout (KO) mice display impaired metabotropic glutamate-receptor-dependent long-term depression (mGluR-LTD) and impaired structural plasticity exclusively at distal Schaffer-collateral synapses. Moreover, by using quantitative proteomics, we find that the Sam68 interactome contains numerous regulators of mRNA translation and synaptic function. This work identifies an important player in Arc expression, provides a general framework for Sam68 regulation of protein synthesis, and uncovers a mechanism that enables the precise spatiotemporal expression of long-term plasticity throughout neurons.

How mRNA Localization and Protein Synthesis Sites Influence Dendritic Protein Distribution and Dynamics

Proteins drive the function of neuronal synapses. The synapses are distributed throughout the dendritic arbor, often hundreds of micrometers away from the soma. It is still unclear how somatic and dendritic sources of proteins shape protein distribution and respectively contribute to local protein changes during synaptic plasticity. Here, we present a unique computational framework describing for a given protein species the dendritic distribution of the mRNA and the corresponding protein in a dendrite. Using CaMKIIα as a test case, our model reveals the key role active transport plays in the maintenance of dendritic mRNA and protein levels and predicts the short and long timescales of protein dynamics. Our model reveals the fundamental role of mRNA localization and dendritic mRNA translation in synaptic maintenance and plasticity in distal compartments. We developed a web application for neuroscientists to explore the dynamics of the mRNA or protein of interest.

Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity

Parkinson disease (PD) is the second most common neurodegenerative disorder and the leading neurodegenerative cause of motor disability. Pathologic accumulation of aggregated alpha synuclein (AS) protein in brain, and imbalance in the nigrostriatal system due to the loss of dopaminergic neurons in the substantia nigra- pars compacta, are hallmark features in PD. AS aggregation and propagation are considered to trigger neurotoxic mechanisms in PD, including mitochondrial deficits and oxidative stress. The eukaryotic elongation factor-2 kinase (eEF2K) mediates critical regulation of dendritic mRNA translation and is a crucial molecule in diverse forms of synaptic plasticity. Here we show that eEF2K activity, assessed by immuonohistochemical detection of eEF2 phosphorylation on serine residue 56, is increased in postmortem PD midbrain and hippocampus. Induction of aggressive, AS-related motor phenotypes in a transgenic PD M83 mouse model also increased brain eEF2K expression and activity. In cultures of dopaminergic N2A cells, overexpression of wild-type human AS or the A53T mutant increased eEF2K activity. eEF2K inhibition prevented the cytotoxicity associated with AS overexpression in N2A cells by improving mitochondrial function and reduced oxidative stress. Furthermore, genetic deletion of the eEF2K ortholog efk-1 in C. elegans attenuated human A53T AS induced defects in behavioural assays reliant on dopaminergic neuron function. These data suggest a role for eEF2K activity in AS toxicity, and support eEF2K inhibition as a potential target in reducing AS-induced oxidative stress in PD.

Dendritic Homeostasis Disruption in a Novel Frontotemporal Dementia Mouse Model Expressing Cytoplasmic Fused in Sarcoma

Cytoplasmic aggregation of fused in sarcoma (FUS) is detected in brain regions affected by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which compose the disease spectrum, FUS proteinopathy. To understand the pathomechanism of ALS-FTD-associated FUS, we examined the behavior and cellular properties of an ALS mouse model overexpressing FUS with nuclear localization signal deletion. Mutant FUS transgenic mice showed hyperactivity, social interactional deficits, and impaired fear memory retrieval, all of which are compatible with FTD phenotypes. Histological analyses showed decreased dendritic spine and synaptic density in the frontal cortex before neuronal loss. Examination of cultured cells confirmed that mutant but not wild-type FUS was associated with decreased dendritic growth, mRNA levels, and protein synthesis in dendrites. These data suggest that cytoplasmic FUS aggregates impair dendritic mRNA trafficking and translation, in turn leading to dendritic homeostasis disruption and the development of FTD phenotypes.

Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease

Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5' untranslated region of TBEV genomic RNA that act as a cis-acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease.

The PICK1 Ca2+ sensor modulates N-methyl-d-aspartate (NMDA) receptor-dependent microRNA-mediated translational repression in neurons

MicroRNAs (miRNAs) are important regulators of localized mRNA translation in neuronal dendrites. The presence of RNA-induced silencing complex proteins in these compartments and the dynamic miRNA expression changes that occur in response to neuronal stimulation highlight their importance in synaptic plasticity. Previously, we demonstrated a novel interaction between the major RNA-induced silencing complex component Argounaute-2 (Ago2) and the BAR (bin/amphiphysin/rvs) domain protein PICK1. PICK1 recruits Ago2 to recycling endosomes in dendrites, where it inhibits miRNA-mediated translational repression. Chemical induction of long-term depression via NMDA receptor activation causes the dissociation of Ago2 from PICK1 and a consequent increase in dendritic miRNA-mediated gene silencing. The mechanism that underlies the regulation of PICK1-Ago2 binding is unknown. In this study, we demonstrate that the PICK1-Ago2 interaction is directly sensitive to Ca2+ ions so that high [Ca2+]free reduces PICK1 binding to Ago2. Mutating a stretch of C-terminal Ca2+-binding residues in PICK1 results in a complete block of NMDA-induced PICK1-Ago2 disassociation in cortical neurons. Furthermore, the same mutant also blocks NMDA-stimulated miRNA-mediated gene silencing. This study defines a novel mechanism whereby elevated [Ca2+] induced by NMDA receptor activation modulates Ago2 and miRNA activity via PICK1. Our work suggests a Ca2+-dependent process to regulate miRNA activity in neurons in response to the induction of long-term depression.

Dynamic Control of Dendritic mRNA Expression by CNOT7 Regulates Synaptic Efficacy and Higher Cognitive Function

Translation of mRNAs in dendrites mediates synaptic plasticity, the probable cellular basis of learning and memory. Coordination of translational inhibitory and stimulatory mechanisms, as well as dendritic transport of mRNA, is necessary to ensure proper control of this local translation. Here, we find that the deadenylase CNOT7 dynamically regulates dendritic mRNA translation and transport, as well as synaptic plasticity and higher cognitive function. In cultured hippocampal neurons, synaptic stimulation induces a rapid decrease in CNOT7, which, in the short-term, results in poly(A) tail lengthening of target mRNAs. However, at later times following stimulation, decreased poly(A) and dendritic localization of mRNA take place, similar to what is observed when CNOT7 is depleted over several days. In mice, CNOT7 is essential for hippocampal-dependent learning and memory. This studyidentifies CNOT7 as an important regulator of RNA transport and translation in dendrites, as well as higher cognitive function.

EEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response.

Soluble oligomers of amyloid-β (Aβ) impair synaptic plasticity, perturb neuronal energy homeostasis, and are implicated in Alzheimer's disease (AD) pathogenesis. Therefore, significant efforts in AD drug discovery research aim to prevent the formation of Aβ oligomers or block their neurotoxicity. The eukaryotic elongation factor-2 kinase (eEF2K) plays a critical role in synaptic plasticity, and couples neurotransmission to local dendritic mRNA translation. Recent evidence indicates that Aβ oligomers activate neuronal eEF2K, suggesting a potential link to Aβ induced synaptic dysfunction. However, a detailed understanding of the role of eEF2K in AD pathogenesis, and therapeutic potential of eEF2K inhibition in AD, remain to be determined. Here, we show that eEF2K activity is increased in postmortem AD patient cortex and hippocampus, and in the hippocampus of aged transgenic AD mice. Furthermore, eEF2K inhibition using pharmacological or genetic approaches prevented the toxic effects of Aβ42 oligomers on neuronal viability and dendrite formation in vitro. We also report that eEF2K inhibition promotes the nuclear factor erythroid 2-related factor (NRF2) antioxidant response in neuronal cells, which was crucial for the beneficial effects of eEF2K inhibition in neurons exposed to Aβ42 oligomers. Accordingly, NRF2 knockdown or overexpression of the NRF2 inhibitor, Kelch-Like ECH-Associated Protein-1 (Keap1), significantly attenuated the neuroprotection associated with eEF2K inhibition. Finally, genetic deletion of the eEF2K ortholog efk-1 reduced oxidative stress, and improved chemotaxis and serotonin sensitivity in C. elegans expressing human Aβ42 in neurons. Taken together, these findings highlight the potential utility of eEF2K inhibition to reduce Aβ-mediated oxidative stress in AD.

MTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors

Mammalian target of rapamycin complex 1 (mTORC1) has an essential role in dendritic mRNA translation and participates in mechanisms underlying alcohol-drinking and reconsolidation of alcohol-related memories. Here, we report that excessive alcohol consumption increases the translation of downstream targets of mTORC1, including collapsin response mediator protein-2 (CRMP-2), in the nucleus accumbens (NAc) of rodents. We show that alcohol-mediated induction of CRMP-2 translation is mTORC1-dependent, leading to increased CRMP-2 protein levels. Furthermore, we demonstrate that alcohol intake also blocks glycogen synthase kinase-3β (GSK-3β)-phosphorylation of CRMP-2, which results in elevated binding of CRMP-2 to microtubules and a concomitant increase in microtubule content. Finally, we show that systemic administration of the CRMP-2 inhibitor lacosamide, or knockdown of CRMP-2 in the NAc decreases excessive alcohol intake. These results suggest that CRMP-2 in the NAc is a convergent point that receives inputs from two signaling pathways, mTORC1 and GSK-3β, that in turn drives excessive alcohol-drinking behaviors.

Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice.

Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cεactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without downregulation of metabotropic glutamate receptor (mGluR) 5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without downregulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults.

Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders.

The fragile X-related disorders are members of the Repeat Expansion Diseases, a group of genetic conditions resulting from an expansion in the size of a tandem repeat tract at a specific genetic locus. The repeat responsible for disease pathology in the fragile X-related disorders is CGG/CCG and the repeat tract is located in the 5′ UTR of the FMR1 gene, whose protein product FMRP, is important for the proper translation of dendritic mRNAs in response to synaptic activation. There are two different pathological FMR1 allele classes that are distinguished only by the number of repeats. Premutation alleles have 55–200 repeats and confer risk of fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Full mutation alleles on the other hand have >200 repeats and result in fragile X syndrome, a disorder that affects learning and behavior. Different symptoms are seen in carriers of premutation and full mutation alleles because the repeat number has paradoxical effects on gene expression: Epigenetic changes increase transcription from premutation alleles and decrease transcription from full mutation alleles. This review will cover what is currently known about the mechanisms responsible for these changes in FMR1 expression and how they may relate to other Repeat Expansion Diseases that also show repeat-mediated changes in gene expression.

Non-coding mechanisms of local mRNA translation in neuronal dendrites

The vast majority of the mammalian genome is transcribed, generating a wealth of transcripts that do not have protein-coding potential. These non-coding RNAs (ncRNAs) have emerged as major mediators of compartmentalized gene expression with many important regulatory functions, and are therefore at the focus of biological research in many cellular systems. The expression of ncRNAs is particularly multifaceted in neurons, as they seem to be expressed in a highly cell-type and activity-dependent manner. Specific subclasses of ncRNAs, especially microRNAs (miRNAs), were implicated in the local regulation of mRNA translation in neuronal dendrites, a process of compartmentalized gene expression that is engaged during synaptic plasticity. Recent discoveries point towards a widespread involvement of ncRNA families in local translation, including less abundant small RNAs (PIWI-interacting RNAs (piRNAs), endogenous small interfering RNAs (endo-siRNAs)) and long ncRNAs (circular RNAs (circRNAs), long intergenic ncRNAs (lincRNAs)). The mechanisms underlying the dendritic transport and the regulatory function of ncRNAs in response to neuronal activity are being elucidated. The emerging picture is an intricate crosstalk between different ncRNA families, mRNAs and RNA-binding proteins (RBPs) that synergistically fine-tune the local dendritic proteome in an activity-dependent manner.

Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is caused by the loss of the fragile X mental retardation protein (FMRP), an RNA binding protein that regulates translation of numerous target mRNAs, some of which are dendritically localized. Our previous biochemical studies using synaptoneurosomes demonstrate a role for FMRP and miR-125a in regulating the translation of PSD-95 mRNA. However, the local translation of PSD-95 mRNA within dendrites and spines, as well as the roles of FMRP or miR-125a, have not been directly studied. Herein, local synthesis of a Venus-PSD-95 fusion protein was directly visualized in dendrites and spines using single-molecule imaging of a diffusion-restricted Venus-PSD-95 reporter under control of the PSD-95 3'UTR. The basal translation rates of Venus-PSD-95 mRNA was increased in cultured hippocampal neurons from Fmr1 KO mice compared with WT neurons, which correlated with a transient elevation of endogenous PSD-95 within dendrites. Following mGluR stimulation with (S)-3,5-dihydroxyphenylglycine, the rate of Venus-PSD-95 mRNA translation increased rapidly in dendrites of WT hippocampal neurons, but not in those of Fmr1 KO neurons or when the binding site of miR125a, previously shown to bind PSD-95 3'UTR, was mutated. This study provides direct support for the hypothesis that local translation within dendrites and spines is dysregulated in FXS. Impairments in the regulated local synthesis of PSD-95, a critical regulator of synaptic structure and function, may affect the spatiotemporal control of PSD-95 levels and affect dendritic spine development and synaptic plasticity in FXS.

HuD interacts with Bdnf mRNA and is essential for activity-induced BDNF synthesis in dendrites.

Highly specific activity-dependent neuronal responses are necessary for modulating synapses to facilitate learning and memory. We present evidence linking a number of important processes involved in regulating synaptic plasticity, suggesting a mechanistic pathway whereby activity-dependent signaling, likely through protein kinase C (PKC)-mediated phosphorylation of HuD, can relieve basal repression of Bdnf mRNA translation in dendrites, allowing for increased TrkB signaling and synaptic remodeling. We demonstrate that the neuronal ELAV family of RNA binding proteins associates in vivo with several Bdnf mRNA isoforms present in the adult brain in an activity-dependent manner, and that one member, HuD, interacts directly with sequences in the long Bdnf 3' untranslated region (3'UTR) and co-localizes with Bdnf mRNA in dendrites of hippocampal neurons. Activation of PKC leads to increased dendritic translation of mRNAs containing the long Bdnf 3'UTR, a process that is dependent on the presence of HuD and its phosphorylation at threonine residues 149 and/or 165. Thus, we found a direct effect of HuD on regulating translation of dendritic Bdnf mRNAs to mediate local and activity-dependent increases in dendritic BDNF synthesis.

Localization and local translation of Arc/Arg3.1 mRNA at synapses: some observations and paradoxes.

Arc is a unique immediate early gene whose expression is induced as synapses are being modified during learning. The uniqueness comes from the fact that newly synthesized Arc mRNA is rapidly transported throughout dendrites where it localizes near synapses that were recently activated. Here, we summarize aspects of Arc mRNA translation in dendrites in vivo, focusing especially on features of its expression that are paradoxical or that donot fit in with current models of how Arc protein operates. Findings from in vivo studies that donot quite fit include: (1) Following induction of LTP in vivo, Arc mRNA and protein localize near active synapses, but are also distributed throughout dendrites. In contrast, Arc mRNA localizes selectively near active synapses when stimulation is continued as Arc mRNA is transported into dendrites; (2) Strong induction of Arc expression as a result of a seizure does not lead to a rundown of synaptic efficacy in vivo as would be predicted by the hypothesis that high levels of Arc cause glutamate receptor endocytosis and LTD. (3) Arc protein is synthesized in the perinuclear cytoplasm rapidly after transcriptional activation, indicating that at least a pool of Arc mRNA is not translationally repressed to allow for dendritic delivery; (4) Increases in Arc mRNA in dendrites are not paralleled by increases in levels of exon junction complex (EJC) proteins. These results of studies of mRNA trafficking in neurons in vivo provide a new perspective on the possible roles of Arc in activity-dependent synaptic modifications.

Old dogs with new tricks: intra-axonal translation of nuclear proteins.

Many different types of polarized eukaryotic cells have been shown to segregate synthesis for some protein subpopulations to cytoplasmic domains distant from their nucleus. For neurons, these distances can be tens-to-thousands fold more than the diameter of the cell body. Both axons and dendrites make use of this localized protein synthesis to bring autonomy to these far reaches of the cytoplasm (Gomes et al., 2014). This local mRNA translation is often used to mount a rapid response to extracellular stimuli encountered by the distal axon and dendrite. Indeed, activating translation of mRNAs residing locally at the synapse or growth cone brings a much more rapid response than could be achieved by transporting new proteins from the cell body. The neuron likely reaps a cost benefit from this mechanism in terms of energy consumption, since multiple protein copies can be generated from a single mRNA through sequential rounds of translation. Localized protein synthesis could also more effectively position a protein near its site of action or even bring an unanticipated novel function to the protein.