Repeated Exposure to D-Amphetamine Decreases Global Protein Synthesis and Regulates the Translation of a Subset of mRNAs in the Striatum

Biever, Anne; Boubaker-Vitre, Jihane; Cutando, Laura; Gracia-Rubio, Irene; Costa-Mattioli, Mauro; Puighermanal, Emma; Valjent, Emmanuel

doi:10.3389/fnmol.2016.00165

Cited by 11 publications

(15 citation statements)

References 64 publications

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“…The phosphorylation of eIF2α inhibits global translation whilst leading to a paradoxical increase in the translation of a subset of uORF-bearing transcripts 47 . Many manipulations of synaptic activity modulate the phosphorylation status of eIF2α in neurons in vivo and in vitro [47][48][49] . Thus, activity-driven eIF2α phosphorylation could act as a switch to enhance the local translational efficiency of uORF-containing transcripts encoding key plasticity-related proteins.…”

Section: Many Transcripts Exhibit Differential Translation Between Nementioning

confidence: 99%

The mRNA translation landscape in the synaptic neuropil

Glock

Biever

Tushev

et al. 2020

Preprint

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To form and modify synaptic connections and store information, neurons continuously remodel their proteomes. The impressive length of dendrites and axons imposes unique logistical challenges to maintain synaptic proteins at locations remote from the transcription source (the nucleus). The discovery of thousands of mRNAs near synapses suggested that neurons overcome distance and gain autonomy by producing proteins locally 1 . It is not known, however if, how and when localized mRNAs are translated into protein. To investigate the translational landscape in neuronal subregions, we performed simultaneous RNA-seq and Ribo-seq from microdissected rodent brain slices to identify and quantify the transcriptome and translatome in cell bodies as well as dendrites and axons (neuropil). More than 4800 transcripts were translated in synaptic regions. Thousands of transcripts were differentially translated between somatic and synaptic regions, with scaffold and signaling molecules mostly arising from local sources. Furthermore, specific mRNA features were identified that regulate the efficiency of mRNA translation. The findings overturn the view that local translation is a minor source of synaptic protein 2 and indicate that on-site translational control is an important mechanism to control synaptic strength. Main textAt neuronal synapses, more than 2500 proteins 1,3 (the "synaptic proteome") act as sensors and effectors to control neuronal excitability, synaptic strength and plasticity. The elaborate morphology and functional compartmentalization of the individual neuron imposes unique logistical challenges to maintain and modify the synaptic proteome at locations remote from the transcription source (i.e. the nucleus). To fulfill the local demand for new protein, neurons localize messenger RNAs (mRNAs) and ribosomes near synapses to produce proteins directly where they are needed 1 . Using highthroughput sequencing, several groups have reported the localization of thousands of transcripts to axons and dendrites (the "local transcriptome") 4-8 .In many cell types, however, it has been shown that the transcript levels do not always predict protein levels 9 , suggesting that mRNA translation is a highly regulated process. Since proteins, rather than mRNAs, drive cellular function, we must therefore determine directly which transcripts are translated into proteins in dendrites and/or axons in vivo (the "local translatome").

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Section: Many Transcripts Exhibit Differential Translation Between Nementioning

confidence: 99%

The mRNA translation landscape in the synaptic neuropil

Glock

Biever

Tushev

et al. 2020

Preprint

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“…More consistent instead, Arc knockout mice showed increased locomotor sensitivity to dopaminergic psychostimulants including amphetamine (Managò et al, 2016 ) and cocaine (Salery et al, 2017 ). Moreover, repeated exposure to amphetamine produce, in the dorsal striatum and nucleus accumbens, a selective increase in a subset of mRNAs including Arc (Biever et al, 2017 ). Finally, the psychostimulant-induced increase in Arc expression seems to be evident mostly in D1-positive medium spiny neurons as well as in NMDA-positive neurons in striatal regions (Biever et al, 2017 ; Salery et al, 2017 ).…”

Section: Arousal/regulatory Systemsmentioning

confidence: 99%

“…Moreover, repeated exposure to amphetamine produce, in the dorsal striatum and nucleus accumbens, a selective increase in a subset of mRNAs including Arc (Biever et al, 2017 ). Finally, the psychostimulant-induced increase in Arc expression seems to be evident mostly in D1-positive medium spiny neurons as well as in NMDA-positive neurons in striatal regions (Biever et al, 2017 ; Salery et al, 2017 ). Overall, these evidence point to Arc as an integrator of D1 and NMDA signaling and demonstrate that Arc genetic disruption causes a predisposition to higher sensitivity to psychostimulants.…”

Section: Arousal/regulatory Systemsmentioning

confidence: 99%

Schizophrenia: What’s Arc Got to Do with It?

Managò

Papaleo

2017

Front. Behav. Neurosci.

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Human studies of schizophrenia are now reporting a previously unidentified genetic convergence on postsynaptic signaling complexes such as the activity-regulated cytoskeletal-associated (Arc) gene. However, because this evidence is still very recent, the neurobiological implication of Arc in schizophrenia is still scattered and unrecognized. Here, we first review current and developing findings connecting Arc in schizophrenia. We then highlight recent and previous findings from preclinical mouse models that elucidate how Arc genetic modifications might recapitulate schizophrenia-relevant behavioral phenotypes following the novel Research Domain Criteria (RDoC) framework. Building on this, we finally compare and evaluate several lines of evidence demonstrating that Arc genetics can alter both glutamatergic and dopaminergic systems in a very selective way, again consistent with molecular alterations characteristic of schizophrenia. Despite being only initial, accumulating and compelling data are showing that Arc might be one of the primary biological players in schizophrenia. Synaptic plasticity alterations in the genetic architecture of psychiatric disorders might be a rule, not an exception. Thus, we anticipate that additional evidence will soon emerge to clarify the Arc-dependent mechanisms involved in the psychiatric-related dysfunctional behavior.

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“…In each experiment, samples from all animal groups were processed in parallel to minimize inter-assay variations. Protein quantification and western blots were performed as described (32, 33). All the information about the antibodies, suppliers, dilutions and references are summarized in the Supplementary Table 1.…”

Section: Methodsmentioning

confidence: 99%

mTOR-RhoA signalling impairments in direct striatal projection neurons induce altered behaviours and striatal physiology in mice

Rial

Puighermanal

Valjent

et al. 2019

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As an integrator of molecular pathways, mTOR has been associated with diseases including neurodevelopmental, psychiatric and neurodegenerative disorders as autism, schizophrenia, and Huntington’s disease. An important brain area involved in all these diseases is the striatum. However, the mechanisms behind how mTOR is involved in striatal physiology and its relative role in distinct neuronal populations in these striatal-related diseases still remain to be clarified.Taking advantage of the D1-mTOR KO mice (males), we combined behavioural, biochemical, electrophysiological and morphological analysis aiming to untangle the role of mTOR in direct pathway striatal projection neurons (dMSNs) and how this would impact on striatal physiology.Our results indicate deep behavioural changes in absence of mTOR in dMSNs such as decreased spontaneous locomotion, impaired social interaction and repetitive behaviour. These were accompanied by a Kv1.1-induced increase in the fast phase of afterhyperpolarization and decreased distal spines density that were mechanistically independent of protein synthesis but dependent of RhoA activity.These results identify mTOR RhoA signaling as an important regulator of striatal functions through an intricate mechanism involving RhoA and culminating in Kv1.1 overfunction, which could be targeted to treat striatal-related mTORopathies.

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Repeated Exposure to D-Amphetamine Decreases Global Protein Synthesis and Regulates the Translation of a Subset of mRNAs in the Striatum

Cited by 11 publications

References 64 publications

The mRNA translation landscape in the synaptic neuropil

The mRNA translation landscape in the synaptic neuropil

Schizophrenia: What’s Arc Got to Do with It?

mTOR-RhoA signalling impairments in direct striatal projection neurons induce altered behaviours and striatal physiology in mice

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