A subthreshold synaptic mechanism regulating BDNF expression and resting synaptic strength DOI Creative Commons
Patricia M. Horvath, Natalí L. Chanaday, Barış Alten

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 36(5), P. 109467 - 109467

Published: Aug. 1, 2021

Recent studies have demonstrated that protein translation can be regulated by spontaneous excitatory neurotransmission. However, the impact of neurotransmitter release on gene transcription remains unclear. Here, we study effects balance between inhibitory and neurotransmission brain-derived neurotrophic factor (BDNF) regulation synaptic plasticity. Blockade events leads to an increase in Bdnf Npas4 through altered calcium signaling, which blocked antagonism NMDA receptors (NMDARs) or L-type voltage-gated channels (VGCCs). Transcription is bidirectionally manipulating inhibitory, but not excitatory, currents. Moreover, blocking multiplicative downscaling strength a manner dependent both BDNF signaling. These results reveal role for signaling sets at rest.

Language: Английский

The emergence and influence of internal states DOI Creative Commons
Steven W. Flavell, Nadine Gogolla, Matthew Lovett-Barron

et al.

Neuron, Journal Year: 2022, Volume and Issue: 110(16), P. 2545 - 2570

Published: May 27, 2022

Language: Английский

Citations

148
The translatome of neuronal cell bodies, dendrites, and axons DOI Creative Commons
Caspar Glock, Anne Biever, Georgi Tushev

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(43)

Published: Oct. 20, 2021

Significance Proteins are the key drivers of neuronal synaptic function. The regulation gene expression is important for formation and modification synapses throughout lifespan. complexity dendrites axons imposes unique challenges protein supply at remote locations. discovery messenger RNAs (mRNAs) ribosomes near has shown that local synthesis represents an solution to this challenge. Here we used RNA sequencing ribosome determine directly population mRNAs present in process translation cell bodies, dendrites, axons. Thousands transcripts were differentially translated between body regions with over 800 exhibiting more dendritic–axonal compartment.

Language: Английский

Citations

129
A NPAS4–NuA4 complex couples synaptic activity to DNA repair DOI Creative Commons
Elizabeth A. Pollina,

Daniel T. Gilliam,

Andrew T. Landau

et al.

Nature, Journal Year: 2023, Volume and Issue: 614(7949), P. 732 - 741

Published: Feb. 15, 2023

Abstract Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of genome across long lifespan postmitotic neurons 1–5 . Whether have acquired specialized protection mechanisms that enable them withstand decades potentially damaging stimuli during periods heightened unknown. Here we identify activity-dependent DNA repair mechanism in which a new form NuA4–TIP60 chromatin modifier assembles activated around inducible, neuronal-specific transcription factor NPAS4. We purify this complex from brain and demonstrate its functions eliciting changes neuronal transcriptomes circuitry. By characterizing landscape activity-induced double-strand breaks brain, show NPAS4–NuA4 binds recurrently damaged regulatory elements recruits additional machinery stimulate their repair. Gene bound by are partially protected against age-dependent accumulation somatic mutations. Impaired signalling leads cascade cellular defects, including dysregulated transcriptional responses, loss control over inhibition instability, all culminate reduce organismal lifespan. In addition, mutations several components NuA4 reported lead neurodevelopmental autism spectrum disorders. Together, these findings couples directly preservation, disruption may contribute developmental disorders, neurodegeneration ageing.

Language: Английский

Citations

85
De-centralizing the Central Dogma: mRNA translation in space and time DOI Creative Commons
Ashley M. Bourke, Andre Schwarz, Erin M. Schuman

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(3), P. 452 - 468

Published: Jan. 19, 2023

As our understanding of the cell interior has grown, we have come to appreciate that most cellular operations are localized, is, they occur at discrete and identifiable locations or domains. These domains contain enzymes, machines, other components necessary carry out regulate these localized operations. Here, review features one such operation: localization translation mRNAs within subcellular compartments observed across types organisms. We describe conceptual advantages "ingredients" mechanisms local translation. focus on nature mRNAs, how travel get this process is regulated. also evaluate current protein synthesis machines (ribosomes) their cadre regulatory elements, factors.

Language: Английский

Citations

55
NPAS4 regulates the transcriptional response of the suprachiasmatic nucleus to light and circadian behavior DOI
Pin Xu, Stefano Berto, Ashwinikumar Kulkarni

et al.

Neuron, Journal Year: 2021, Volume and Issue: 109(20), P. 3268 - 3282.e6

Published: Aug. 19, 2021

Language: Английский

Citations

69
Excitation–transcription coupling, neuronal gene expression and synaptic plasticity DOI
Huan Ma, Houda G. Khaled, Xiaohan Wang

et al.

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(11), P. 672 - 692

Published: Sept. 29, 2023

Language: Английский

Citations

35
Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding DOI Creative Commons
Ezgi Hacisuleyman, Caryn Hale,

Natalie Noble

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(5), P. 822 - 835

Published: April 8, 2024

Abstract Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved how they regulated unclear. In this study, to monitor depolarization impacts local biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming protein expression, where proteins weakly correlated. For subset pre-localized messages, increased translation upstream open reading frames (uORFs) their downstream coding sequences, enabling localized production long-term potentiation, cell signaling energy metabolism. This activity-dependent was accompanied phosphorylation recruitment non-canonical initiation factor eIF4G2, translated uORFs were sufficient confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism uORF control eIF4G2 couples activity remodeling.

Language: Английский

Citations

16
Emerging Roles for 3′ UTRs in Neurons DOI Open Access
Bongmin Bae, Pedro Miura

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(10), P. 3413 - 3413

Published: May 12, 2020

The 3' untranslated regions (3' UTRs) of mRNAs serve as hubs for post-transcriptional control the targets microRNAs (miRNAs) and RNA-binding proteins (RBPs). Sequences in UTRs confer alterations mRNA stability, direct localization to subcellular regions, impart translational control. Thousands are localized compartments neurons-including axons, dendrites, synapses-where they thought undergo local translation. Despite an established role UTR sequences imparting neurons, specific RNA structural features at play remain poorly understood. nervous system selectively expresses longer isoforms via alternative polyadenylation (APA). regulation APA neurons neuronal functions starting be uncovered. Surprising roles emerging beyond protein synthesis include RBP delivery scaffolds regulators splicing. Evidence is also that can cleaved, leading stable, isolated fragments which unknown function. Mutations implicated several neurological disorders-more studies needed uncover how these mutations impact gene what their relationship disease severity.

Language: Английский

Citations

65
Initial memory consolidation and the synaptic tagging and capture hypothesis DOI
Kosuke Okuda, Kristoffer Højgaard, Lucia Privitera

et al.

European Journal of Neuroscience, Journal Year: 2020, Volume and Issue: 54(8), P. 6826 - 6849

Published: July 10, 2020

Abstract Everyday memories are retained automatically in the hippocampus and then decay very rapidly. Memory retention can be boosted when novel experiences occur shortly before or after time of memory encoding via a stabilization process called "initial consolidation." The dopamine release new protein synthesis during experience crucial for this novelty‐induced boost. mechanisms underlying initial consolidation not well‐understood, but synaptic tagging capture (STC) hypothesis provides conceptual basis plasticity events occurring consolidation. In review, we provide an overview STC its relevance to dopaminergic signalling, order explore cellular molecular hippocampus. We summarize electrophysiological processes based on evidence from two‐pathway experiments behavioural hypothesis, which translates into related hypothesis. also discuss function two types molecules, "synaptic tags" "plasticity‐related proteins," have role describe candidate molecules roles tag plasticity‐related proteins interpret their candidacy ex vivo , recent cutting‐edge optical imaging experiments. Lastly, direction future studies advance our understanding process, critical

Language: Английский

Citations

62
Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases DOI Creative Commons

Jian Fu,

Ouyang Guo,

Zhihang Zhen

et al.

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: Dec. 1, 2020

Signaling from the synapse to nucleus is mediated by integration and propagation of both membrane potential changes (postsynaptic potentials) intracellular second messenger cascades. The electrical postsynaptic potentials allows for rapid neural information processing, while propagating pathways link synaptic activity transcription genes required neuronal survival adaptive (plasticity) underlying circuit formation learning. activity-induced calcium signals cell a major synapse-to-nucleus communication pathway. Neuronal PAS domain protein 4 (Npas4) recently discovered calcium-dependent factor that regulates activation involved in homeostatic regulation excitatory-inhibitory balance, which critical formation, function, ongoing plasticity, as well defense against diseases such epilepsy. Here, we summarize recent findings on neuroprotective functions Npas4 therapeutic target treatment acute chronic central nervous system.

Language: Английский

Citations

54