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NMDAR mediated dynamic changes in m⁶A inversely correlates with neuronal translation.

ABSTRACT: Epitranscriptome modifications are crucial in translation regulation and essential for maintaining cellular homeostasis. N6 methyladenosine (m⁶A) is one of the most abundant and well-conserved epitranscriptome modifications, which is known to play a pivotal role in diverse aspects of neuronal functions. However, the role of m⁶A modifications with respect to activity-mediated translation regulation and synaptic plasticity has not been studied. Here, we investigated the role of m⁶A modification in response to NMDAR stimulation. We have consistently observed that 5 min NMDAR stimulation causes an increase in eEF2 phosphorylation. Correspondingly, NMDAR stimulation caused a significant increase in the m⁶A signal at 5 min time point, correlating with the global translation inhibition. The NMDAR induced increase in the m⁶A signal is accompanied by the redistribution of the m⁶A marked RNAs from translating to the non-translating pool of ribosomes. The increased m⁶A levels are well correlated with the reduced FTO levels observed on NMDAR stimulation. Additionally, we show that inhibition of FTO prevents NMDAR mediated changes in m⁶A levels. Overall, our results establish RNA-based molecular readout which corelates with the NMDAR-dependent translation regulation which helps in understanding changes in protein synthesis.

SUBMITTER: Gowda NKC

PROVIDER: S-EPMC9256623 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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NMDAR mediated dynamic changes in m6A inversely correlates with neuronal translation.

Gowda Naveen Kumar Chandappa NKC Nawalpuri Bharti B Ramakrishna Sarayu S Jhaveri Vishwaja V Muddashetty Ravi S RS

Scientific reports 20220705 1

Epitranscriptome modifications are crucial in translation regulation and essential for maintaining cellular homeostasis. N6 methyladenosine (m6A) is one of the most abundant and well-conserved epitranscriptome modifications, which is known to play a pivotal role in diverse aspects of neuronal functions. However, the role of m6A modifications with respect to activity-mediated translation regulation and synaptic plasticity has not been studied. Here, we investigated the role ...[more]

PMID: 35790863

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Project description:Backgroundβ Amyloid (Aβ)-mediated neuronal hyperactivity, a key feature of the early stage of Alzheimer's disease (AD), is recently proposed to be initiated by the suppression of glutamate reuptake. Nevertheless, the underlying mechanism by which the impaired glutamate reuptake causes neuronal hyperactivity remains unclear. Chronic suppression of the glutamate reuptake causes accumulation of ambient glutamate that could diffuse from synaptic sites at the dendrites to the soma to elevate the tonic activation of somatic N-methyl-D-aspartate receptors (NMDARs). However, less attention has been paid to the potential role of tonic activity change in extrasynaptic glutamate receptors (GluRs) located at the neuronal soma on generation of neuronal hyperactivity.MethodsWhole-cell patch-clamp recordings were performed on CA1 pyramidal neurons in acute hippocampal slices exposed to TFB-threo-β-benzyloxyaspartic acid (TBOA) or human Aβ1-42 peptide oligomer. A series of dendritic patch-clamp recordings were made at different distances from the soma to identify the location of the changes in synaptic inputs. Moreover, single-channel recording in the cell-attached mode was performed to investigate the activity changes of single NMDARs at the soma.ResultsBlocking glutamate uptake with either TBOA or the human Aβ1-42 peptide oligomer elicited potentiation of synaptic inputs in CA1 hippocampal neurons. Strikingly, this potentiation specifically occurred at the soma, depending on the activation of somatic GluN2B-containing NMDARs (GluN2B-NMDARs) and accompanied by a substantial and persistent increment in the open probability of somatic NMDARs. Blocking the activity of GluN2B-NMDARs at the soma completely reversed both the TBOA-induced or the Aβ1-42-induced somatic potentiation and neuronal hyperactivity.ConclusionsThe somatic potentiation of synaptic inputs may represent a novel amplification mechanism that elevates cell excitability and thus contributes to neuronal hyperactivity initiated by impaired glutamate reuptake in AD.

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NMDAR mediated dynamic changes in m⁶A inversely correlates with neuronal translation.

Publications

NMDAR mediated dynamic changes in m<sup>6</sup>A inversely correlates with neuronal translation.

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