Bursts of high‐frequency stimulation trigger rapid delivery of pre‐existing α‐CaMKII mRNA to synapses: a mechanism in dendritic protein synthesis during long‐term potentiation in adult awake rats

Håvik, Bjarte; Røkke, Håvard; Bårdsen, Kjetil; Davanger, Svend; Bramham, Clive R.

doi:10.1046/j.1460-9568.2003.02712.x

Cited by 85 publications

(73 citation statements)

References 86 publications

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“…To determine relative distribution of tPA mRNA between crude homogenate and SN, we used an end-point RT-PCR analysis (Havik et al, 2003). Briefly, total RNA was prepared from rat hippocampus or SN, and 0.5-4 g was reversetranscribed for 1 hr at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Rapid, Activity-Induced Increase in Tissue Plasminogen Activator Is Mediated by Metabotropic Glutamate Receptor-Dependent mRNA Translation

Shin¹,

Kundel²,

Wells³

2004

J. Neurosci.

128

116

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Long-term synaptic plasticity is both protein synthesis-dependent and synapse-specific. Therefore, the identity of the newly synthesized proteins, their localization, and mechanism of regulation are critical to our understanding of this process. Tissue plasminogen activator (tPA) is a secreted protease required for some forms of long-term synaptic plasticity. Here, we show tPA activity is rapidly increased in hippocampal neurons after glutamate stimulation. This increase in tPA activity corresponds to an increase in tPA protein synthesis that results from the translational activation of mRNA present at the time of stimulation. Furthermore, the mRNA encoding tPA is present in dendrites and is rapidly polyadenylated after glutamate stimulation. Both the polyadenylation of tPA mRNA and the subsequent increase in tPA protein is dependent on metabotropic glutamate receptor (mGluR) activation. A similar mGluR-dependent increase in tPA activity was detected after stimulation of a synaptic fraction isolated from the hippocampus, suggesting tPA synthesis is occurring in the synaptodendritic region. Finally, we demonstrate that tPA mRNA is bound by the mRNA-binding protein CPEB (cytoplasmic polyadenylation element binding protein-1), a protein known to regulate mRNA translation via polyadenylation. These results indicate that neurons are capable of synthesizing a secreted protein in the synaptic region, that mGluR activation induces mRNA polyadenylation and translation of specific mRNA, and suggest a model for synaptic plasticity whereby translational regulation of an immediate early gene precedes the increase in gene transcription.

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Section: Methodsmentioning

confidence: 99%

Rapid, Activity-Induced Increase in Tissue Plasminogen Activator Is Mediated by Metabotropic Glutamate Receptor-Dependent mRNA Translation

Shin¹,

Kundel²,

Wells³

2004

J. Neurosci.

128

116

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“…A panel of proteins was chosen to evaluate the specificity of the Arc knockdown. mRNA encoding ␣-CaMKII is stored in dendrites, and local translation of this message affects the size of the PSD and development of late LTP (Miller et al, 2002;Havik et al, 2003). The scaffolding protein PSD-95 is part of the core PSD complex of excitatory synapses, in which it colocalizes with Arc and CaMKII (Lyford et al, 1995;Husi et al, 2000;Moga et al, 2004).…”

Section: Dynamic Role Of Arc In Ltp Expression and Consolidationmentioning

confidence: 99%

Sustained Arc/Arg3.1 Synthesis Controls Long-Term Potentiation Consolidation through Regulation of Local Actin Polymerization in the Dentate GyrusIn Vivo

Messaoudi¹,

Kanhema²,

Soulé³

et al. 2007

J. Neurosci.

419

463

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New gene expression is necessary for long-term potentiation (LTP) consolidation, yet roles for specific activity-induced mRNAs have not been defined. Here we probed the dynamic function of activity-induced Arc (activity-regulated cytoskeletal-associated protein)/Arg3.1 (activity-regulated gene 3.1 protein homolog) mRNA using brief, local infusions of antisense (AS) oligodeoxynucleotides at multiple time points during dentate gyrus LTP in vivo. Surprisingly, early Arc synthesis is necessary for early expression of LTP, whereas sustained synthesis is required to generate stably modified synapses. AS application 2 h after LTP induction results in a rapid and permanent reversal of LTP. This reversal is associated with rapid knockdown of upregulated Arc, dephosphorylation of actin depolymerization factor/cofilin, and loss of nascent filamentous actin (F-actin) at synaptic sites. Infusion of the F-actin stabilizing drug jasplakinolide during LTP maintenance blocks the ability of AS to reverse LTP. These results couple activity-induced expression of Arc to expansion of the actin cytoskeleton underlying enduring LTP. Furthermore, Arc synthesis is required for both the induction and consolidation of LTP elicited by local BDNF infusion, thus identifying Arc as a key molecular effector of BDNF in synaptic plasticity.

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“…Stimuli that activate NMDA or neurotrophic receptor tyrosine kinase 2 (TrkB) receptors drive specific BDNF mRNA isoforms into distal dendrites of hippocampal neurons (15). High-frequency stimulation of perforant path projections to the dentate gyrus has been shown to direct localization of the mRNA encoding the immediate-early gene Arc selectively and specifically to activated dendritic lamina (16) and to drive localization of preexisting CaMKIIα mRNA into synaptosome fractions (17). Together, these findings indicate that specific transcripts undergo constitutive as well as developmental-and activity-dependent localization to distinct subcellular compartments.…”

mentioning

confidence: 99%

Identification of a cis-acting element that localizes mRNA to synapses

Meer

Wang²,

Sangmok³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Messenger RNA (mRNA) localization and regulated translation can spatially restrict gene expression to each of the thousands of synaptic compartments formed by a single neuron. Although cisacting RNA elements have been shown to direct localization of mRNAs from the soma into neuronal processes, less is known about signals that target transcripts specifically to synapses. In Aplysia sensory-motor neuronal cultures, synapse formation rapidly redistributes the mRNA encoding the peptide neurotransmitter sensorin from neuritic shafts into synapses. We find that the export of sensorin mRNA from soma to neurite and the localization to synapse are controlled by distinct signals. The 3′ UTR is sufficient for export into distal neurites, whereas the 5′ UTR is required for concentration of reporter mRNA at synapses. We have identified a 66-nt element in the 5′ UTR of sensorin that is necessary and sufficient for synaptic mRNA localization. Mutational and chemical probing analyses are consistent with a role for secondary structure in this process.M essenger RNA (mRNA) localization and regulated translation provide a means of spatially restricting gene expression within distinct subcellular compartments. In the brain, local protein synthesis is critical to the development and experience-driven refinement of neural circuits, playing roles in axon guidance, synaptogenesis, and synaptic plasticity (1, 2). A large but select population of transcripts localizes to axons and dendrites (3-8), indicating that local translation subserves diverse cell biological functions. Where studied, the localization of mRNAs to axons or dendrites has been shown to depend on cisacting localization elements (LEs) usually found in the 3′ UTR, although occasionally present in the coding sequence or 5′ UTR (1, 2, 9). These cis-acting mRNA LEs recruit specific transacting RNA binding proteins, and the resulting messenger ribonucleoproteins are packaged into RNA transport granules that interact with molecular motors to be delivered to their final subcellular destination (10-12).In situ hybridization studies in neurons indicate that localized mRNAs in neurons are targeted to distinct subcellular compartments and domains within neuronal processes. For example, MAP2 mRNA concentrates within proximal dendrites, whereas calcium-calmodulin dependent protein kinase IIα (CaMKIIα) mRNA extends to distal dendrites (13). mRNA localization also seems to be dynamically regulated during development and with activity. In mature neurons, β-actin mRNA localizes to dendrites, and its concentration to distal dendrites is stimulated by depolarization (14). Stimuli that activate NMDA or neurotrophic receptor tyrosine kinase 2 (TrkB) receptors drive specific BDNF mRNA isoforms into distal dendrites of hippocampal neurons (15). High-frequency stimulation of perforant path projections to the dentate gyrus has been shown to direct localization of the mRNA encoding the immediate-early gene Arc selectively and specifically to activated dendritic lamina (16) and to drive localizati...

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Bursts of high‐frequency stimulation trigger rapid delivery of pre‐existing α‐CaMKII mRNA to synapses: a mechanism in dendritic protein synthesis during long‐term potentiation in adult awake rats

Cited by 85 publications

References 86 publications

Rapid, Activity-Induced Increase in Tissue Plasminogen Activator Is Mediated by Metabotropic Glutamate Receptor-Dependent mRNA Translation

Rapid, Activity-Induced Increase in Tissue Plasminogen Activator Is Mediated by Metabotropic Glutamate Receptor-Dependent mRNA Translation

Sustained Arc/Arg3.1 Synthesis Controls Long-Term Potentiation Consolidation through Regulation of Local Actin Polymerization in the Dentate GyrusIn Vivo

Identification of a cis-acting element that localizes mRNA to synapses

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