REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors

Rodenas-Ruano, Alma; Chávez, Andrés E.; Cossio, M.; Castillo, Pablo E.; Zukin, R. Suzanne

doi:10.1038/nn.3214

Cited by 176 publications

(166 citation statements)

References 52 publications

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“…Western blotting was performed as described in ref. 38. Brains were removed and the neocortex was rapidly dissected in ice-cold homogenization buffer (320 mM sucrose, 1 mM EDTA, 5 mM Tris, pH 7.4; 0.25 mM DTT and protease and phosphatase inhibitors were added immediately before use).…”

Section: Methodsmentioning

confidence: 99%

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Sawicka

Pyronneau

Chao

et al. 2016

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

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Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.F ragile X syndrome (FXS) is the most common heritable form of intellectual disability and a leading genetic cause of autism. Individuals with FXS typically suffer from a range of cognitive and behavioral deficits that can include anxiety, stereotypic movements, hyperactivity, seizures, and aggression, as well as social deficits typical of autism (1). FXS is caused by transcriptional silencing or mutation of the FMR1 gene encoding the RNA-binding protein, FMRP (fragile X mental retardation protein). FMRP binds to >1,000 mRNAs, including transcripts encoding both preand postsynaptic proteins important for synaptic function, and represses their translation via ribosome stalling (2). Loss of FMRP expression in fragile X syndrome would be expected to cause translational derepression of these target mRNAs.FMRP is strategically localized to dendrites, dendritic spines, axons, and cell bodies to control protein synthesis. Loss of FMRP causes enhanced protein synthesis, which can lead to altered spine morphology, synaptic circuits, and synaptic function with robust effects on higher cognitive function. The excessive, unchecked protein synthesis and impaired stimulus-induced protein synthesis are considered to be major contributors to the pathophysiology of fragile X (3-5). Increased protein synthesis has been demonstrated in whole-animal st...

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Section: Methodsmentioning

confidence: 99%

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Sawicka

Pyronneau

Chao

et al. 2016

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

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“…Postnatal maternal separation alters H3K27 tri-methylation at the gene encoding N-methyl-D-aspartate receptor (Grin2b) in the hippocampus with implications for learning and memory (Rodenas-Ruano et al, 2012). Within the amygdala, maternal separation has been found to increase DNA methylation of the neurotensin receptor (Ntsr1) associated with reduced Ntsr1 mRNA and increased freezing behavior during fear conditioning (Toda et al, 2014).…”

Section: Maternal Neglect In Rodents and Primatesmentioning

confidence: 99%

Early-Life Experience, Epigenetics, and the Developing Brain

Kundaković

Champagne

2014

Neuropsychopharmacol

243

182

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Development is a dynamic process that involves interplay between genes and the environment. In mammals, the quality of the postnatal environment is shaped by parent-offspring interactions that promote growth and survival and can lead to divergent developmental trajectories with implications for later-life neurobiological and behavioral characteristics. Emerging evidence suggests that epigenetic factors (ie, DNA methylation, posttranslational histone modifications, and small noncoding RNAs) may have a critical role in these parental care effects. Although this evidence is drawn primarily from rodent studies, there is increasing support for these effects in humans. Through these molecular mechanisms, variation in risk of psychopathology may emerge, particularly as a consequence of early-life neglect and abuse. Here we will highlight evidence of dynamic epigenetic changes in the developing brain in response to variation in the quality of postnatal parent-offspring interactions. The recruitment of epigenetic pathways for the biological embedding of early-life experience may also have transgenerational consequences and we will describe and contrast two routes through which this transmission can occur: experience dependent vs germline inheritance. Finally, we will speculate regarding the future directions of epigenetic research and how it can help us gain a better understanding of the developmental origins of psychiatric dysfunction.

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“…Corepressors, in turn, recruit multiple chromatin remodeling factors that ultimately repress gene transcription by densely packing the genomic material. REST levels decrease during brain development and are relatively low in mature neurons (8); however, increased REST expression has been reported in a large array of brain pathologies. In this regard, whether the increase of REST is protective or deleterious for neural cells is still debated.…”

mentioning

confidence: 98%

Regulation of neural gene transcription by optogenetic inhibition of the RE1-silencing transcription factor

Paonessa

Criscuolo

Sacchetti

et al. 2015

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

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Optogenetics provides new ways to activate gene transcription; however, no attempts have been made as yet to modulate mammalian transcription factors. We report the light-mediated regulation of the repressor element 1 (RE1)-silencing transcription factor (REST), a master regulator of neural genes. To tune REST activity, we selected two protein domains that impair REST-DNA binding or recruitment of the cofactor mSin3a. Computational modeling guided the fusion of the inhibitory domains to the light-sensitive Avena sativa lightoxygen-voltage-sensing (LOV) 2-phototrophin 1 (AsLOV2). By expressing AsLOV2 chimeras in Neuro2a cells, we achieved light-dependent modulation of REST target genes that was associated with an improved neural differentiation. In primary neurons, light-mediated REST inhibition increased Na + -channel 1.2 and brain-derived neurotrophic factor transcription and boosted Na + currents and neuronal firing. This optogenetic approach allows the coordinated expression of a cluster of genes impinging on neuronal activity, providing a tool for studying neuronal physiology and correcting gene expression changes taking place in brain diseases.

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REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors

Cited by 176 publications

References 52 publications

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Early-Life Experience, Epigenetics, and the Developing Brain

Regulation of neural gene transcription by optogenetic inhibition of the RE1-silencing transcription factor

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