REST-Dependent Presynaptic Homeostasis Induced by Chronic Neuronal Hyperactivity

Pecoraro-Bisogni, F; Lignani, Gabriele; Contestabile, Andrea; Castroflorio, Enrico; Pozzi, Davide; Rocchi, Anna; Prestigio, Cosimo; Orlando, Marta; Valente, Pierluigi; Massacesi, Manuela; Baldelli, Pietro

doi:10.1007/s12035-017-0698-9

Cited by 28 publications

(42 citation statements)

References 58 publications

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“…Aging conditional REST-deficient mice exhibit increased cortical neural activity and hyperexcitability. This is consistent with previous studies in neuronal cell culture which suggest that REST maintains neural network homeostasis by buffering changes in neural excitation 26,27 .…”

Section: Discussionsupporting

confidence: 93%

Regulation of lifespan by neural excitation and REST

Zullo

Drake

Aron

et al. 2019

Nature

186

164

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The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex characterized by downregulation of genes related to neural excitation and synaptic function. In the model system C. elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The REST transcription factor is upregulated in humans with extended longevity and represses excitationrelated genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during aging. Similarly, loss-of-function mutations in the C. elegans REST orthologs Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Discussionsupporting

confidence: 93%

Regulation of lifespan by neural excitation and REST

Zullo

Drake

Aron

et al. 2019

Nature

186

164

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“…Alterations of REST expression and/or activity have been associated with the onset of epilepsy, although the precise role of this factor in the progression of the pathology is still debated, and likely depends on the model employed and on the cell type analyzed (Hu et al, 2011;Liu et al, 2012;Patterson et al, 2017). Our findings are consistent with previous studies, which implicated REST in maintaining neuronal homeostasis and reducing the hyperexcitation of the network (Pozzi et al, 2013;Pecoraro-Bisogni et al, 2018;Zullo et al, 2019).…”

Section: Discussionsupporting

confidence: 90%

Mild Inactivation of RE-1 Silencing Transcription Factor (REST) Reduces Susceptibility to Kainic Acid-Induced Seizures

Carminati

Buffolo

Rocchi

et al. 2020

Front. Cell. Neurosci.

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RE-1 Silencing Transcription factor (REST) controls several steps in neural development by modulating the expression of a wide range of neural genes. Alterations in REST expression have been associated with the onset of epilepsy; however, whether such alterations are deleterious or represent a protective homeostatic response remains elusive. To study the impact of REST modulation on seizure propensity, we developed a tool for its negative modulation in vivo. The tool is composed of the paired-amphipathic helix 1 (PAH1) domain, a competitive inhibitor of REST activation by mSin3, fused to the light-oxygen-voltage sensing 2 (LOV2) domain of Avena sativa phototropin 1, a molecular switch to alternatively hide or expose the PAH1 inhibitor. We employed the C450A and I539E light-independent AsLOV2 variants to mimic the closed (inactive) and open (active) states of LOV2-PAH1, respectively. Recombinant AAV1/2 viral particles (rAAVs) allowed LOV2-PAH1 expression in HEK293T cells and primary neurons, and efficiently transduced hippocampal neurons in vivo. mRNA expression analysis revealed an increased expression of several neuronal genes in the hippocampi of mice expressing the open probe. AAV-transduced mice received a single dose of kainic acid (KA), a treatment known to induce a transient increase of REST levels in the hippocampus. Remarkably, mice expressing the active variant displayed a reduced number of KA-induced seizures, which were less severe compared to mice carrying the inactive probe. These data support the validity of our tool to modulate REST activity in vivo and the potential impact of REST modulation on epileptogenesis.

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“…Notably, miR-218 can act also as negative regulator and several mRNAs have been experimentally validated as genuine targets, including the RE-1 silencing transcription factor (REST) [72]. REST is a transcriptional repressor of GluA2 and participates in synaptic homeostasis by reducing the strength of excitatory synapses [73][74][75][76]. Thus, it is possible that miR-218 exerts a concerted action on GluA2 translation and AMPA receptor composition through a direct stimulatory action on the 3'UTR of GluR2 mRNA and by an indirect inhibitory action on the 3'UTR of REST mRNA that in turn relieves the REST-mediated inhibition of Gria2 transcription.…”

mentioning

confidence: 99%

Neurite-Enriched MicroRNA-218 Stimulates Translation of the GluA2 Subunit and Increases Excitatory Synaptic Strength

et al. 2019

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Local control of protein translation is a fundamental process for the regulation of synaptic plasticity. It has been demonstrated that the local protein synthesis occurring in axons and dendrites can be shaped by numerous mechanisms, including miRNA-mediated regulation. However, several aspects underlying this regulatory process have not been elucidated yet.Here we analyze the differential miRNA profile in cell bodies and neurites of primary hippocampal neurons and find an enrichment of the precursor and mature forms of miR-218 in the neuritic projections. We show that miR-218 abundance is regulated during hippocampal development and by chronic silencing or activation of neuronal network. Overexpression and knockdown of miR-218 demonstrated that miR-218 targets the mRNA encoding the GluA2 subunit of AMPA receptors and modulates its expression. At the functional level, miR-218 overexpression increases glutamatergic synaptic transmission at both single neuron and network levels. Our data demonstrate a key role for miR-218 in the regulation of AMPAmediated excitatory transmission and in the homeostatic regulation of synaptic plasticity.

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REST-Dependent Presynaptic Homeostasis Induced by Chronic Neuronal Hyperactivity

Cited by 28 publications

References 58 publications

Regulation of lifespan by neural excitation and REST

Regulation of lifespan by neural excitation and REST

Mild Inactivation of RE-1 Silencing Transcription Factor (REST) Reduces Susceptibility to Kainic Acid-Induced Seizures

Neurite-Enriched MicroRNA-218 Stimulates Translation of the GluA2 Subunit and Increases Excitatory Synaptic Strength

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