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Neuronal activity induced by BDNF prompts chromatin remodeling at regulatory elements associated with neuropsychiatric traits [mouse]

ABSTRACT: Neuronal activity induced by Brain-Derived Neurotrophic Factor (BDNF) is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. Molecular mechanisms of BDNF promoting cellular survival and synaptic plasticity have been intensely studied, yet its role in genome regulation is obscure. Here, through temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon BDNF treatment or depolarization (KCl), we identified BDNF-specific chromatin-to-gene expression programs. Our analyses revealed that enhancer activation is an early event in the regulatory control of BDNF treated neurons, where bZIP pioneered chromatin opening and co-regulatory transcription factors (Homeobox, EGRs, and CTCF) cooperate to induce fine-grained transcription. Deleting such cis-regulatory sequences decreased the BDNF mediated expression of Arc, a key regulator of synaptic plasticity. Furthermore, BDNF-induced accessible regions are linked to preferential exon usage of neurodevelopmental disorder related genes and heritability of neuronal complex traits. In conclusion, this work provides a comprehensive view of BDNF-mediated genome regulatory features and emphasizes the usage of genomic approaches on dissecting mammalian neuronal activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE166959 | GEO | 2022/09/01

REPOSITORIES: GEO

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Histone methylation by the Kleefstra Syndrome protein EHMT1 mediates homeostatic synaptic scaling.

Project description:Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra syndrome-associated protein, EHMT1, plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vivo or in vivo. These findings suggest that changes in chromatin state through H3K9me2 governs a repressive program to achieve synaptic scaling. 12 samples (4 conditions in biological triplicate), 3 wt, 3 wt tetradotoxin treated, 3 k.d., 3 k.d. tetradotoxin treated

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Histone methylation by the Kleefstra Syndrome protein EHMT1 mediates homeostatic synaptic scaling.

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2017-02-27 | GSE78055 | GEO

BDNF stimulation of protein synthesis in cortical neurons requires the eIF4E kinase Mnk1

Project description:Although the Mnks have been known for >15 years, their roles in the regulation of protein synthesis have remained obscure. Here we explore how BDNF stimulates protein synthesis in cortical neurons. Using a combination of pharmacological and genetic approaches, we show that this effect depends on MEK/ERK signaling and on the downstream kinase, Mnk1, which phosphorylates eIF4E. Translation initiation is mediated by the interaction of eIF4E with the m7GTP cap of mRNA and with eIF4G. The latter interaction is inhibited by the interactions of eIF4E with partner proteins such as CYFIP1, which together with its partner, FMRP acts as a translational repressor. We find that BDNF induces the release of CYFIP1 from eIF4E, and that this depends on Mnk1. Finally, using a novel combination of BONCAT and SILAC, we identify the a subset of proteins whose synthesis is upregulated by BDNF signalling via Mnk1 in neurons. The This subset of Mnk1-sensitive proteins are enriched for functions involved in neurotransmission and synaptic plasticity. Additionally, we find significant overlap between our subset of Mnk1 Mnk1-sensitive proteins and proteins encoded by known FMRP-binding mRNAs. Taken together, our data implicate Mnk1 as a key component of BDNF-mediated translational regulation in neurons.

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Project description:Neuronal protein synthesis is required for long-lasting plasticity and long-term memory consolidation. Dephosphorylation of eukaryotic initiation factor 2α is one of the key translational control events that is required to increase de novo protein synthesis that underlies long-lasting plasticity and memory consolidation. Here, we interrogate the molecular pathways of translational control that are triggered by neuronal stimulation with brain-derived neurotrophic factor (BDNF), which results in eIF2α dephosphorylation and de novo protein synthesis. Primary rodent neurons exposed to BDNF displayed elevated translation, but not transcription, of GADD34, which facilitates eIF2α dephosphorylation and subsequent de novo protein synthesis. Furthermore, GADD34 requires G-actin generated by cofilin to dephosphorylate eIF2α and enhance protein synthesis. Finally, GADD34 is required for BDNF-induced translation of synaptic plasticity-related proteins. Overall, we provide evidence that neurons repurpose GADD34, an effector of the Integrated Stress Response, as an orchestrator of rapid increases in eIF2-dependent translation in response to plasticity-inducing stimuli.

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