Translation of BDNF-gene transcripts with short 3′ UTR in hippocampal CA1 neurons improves memory formation and enhances synaptic plasticity-relevant signaling pathways

Wang, Man; Li, Dongxue; Yun, Di; Zhuang, Yinghan; Repunte‐Canonigo, Vez; Sanna, Pietro Paolo; Behnisch, Thomas

doi:10.1016/j.nlm.2016.07.004

Cited by 15 publications

(17 citation statements)

References 81 publications

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“…In the final set of experiments, we investigated whether DNMT3a1 degradation occurs in vivo as a result of CA1-dependent learning and whether this degradation and memory formation is neddylation-sensitive. Formation of a memory for the spatial location of objects in an open field ( Fig 6A) requires synaptic activity of CA1 neurons (Assini et al, 2009;Haettig et al, 2013) and is responsive to changes in the expression of BDNF (Intlekofer et al, 2013;Wang et al, 2017). We observed that DNMT3a1 protein levels were reduced in mice three hours following training ( Fig 6B and C).…”

Section: Dnmt3a1 Is Degraded In the Hippocampus As A Results Of Learningmentioning

confidence: 76%

“…Moreover, in this study we propose a long-distance signaling pathway that can provide a potential link between different observations. Converging evidence suggests that NMDAR function in the dorsal CA1 area is critical for novel object location memory (Assini et al, 2009;Haettig et al, 2013) and increased BDNF expression in the hippocampal CA1 region supports object location learning (Intlekofer et al, 2013;Wang et al, 2017). We have, therefore, chosen BDNF as a paradigmatic example for our studies, which is one of the target genes that undergoes promoter-specific DNA demethylation in the CA1 region of the hippocampus during memory consolidation (Lubin et al, 2005) and impaired spatial learning and memory as well as attenuated CA1-LTP have been reported following a forebrain specific DNMT1 and -3 gene knockout in principal neurons (Feng et al, 2010, Morris et al, 2014.…”

Section: Discussionmentioning

confidence: 99%

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Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus

Bayraktar

Yuanxiang

Gomes

et al. 2019

Preprint

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DNA-methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3a1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit.Interestingly, synaptic NMDAR drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3a1 and results in deficits of promoter methylation of activity-dependent genes, synaptic plasticity as well as memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively the data show that GluN2A containing NMDAR control synapseto-nucleus signaling that links plasticity-relevant signals to activity-dependent DNAmethylation involved in memory formation.

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Section: Dnmt3a1 Is Degraded In the Hippocampus As A Results Of Learningmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus

Bayraktar

Yuanxiang

Gomes

et al. 2019

Preprint

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“…Acute hippocampal slices were prepared from 4-to 8-week-old male mice as described previously (Huang et al, 2015;Weng et al, 2016;Wang et al, 2017;Yun et al, 2018;Li et al, 2019) with slight modifications to ensure the connectivity of the hippocampal formation with the entorhinal cortex in vitro according to Xiong et al (2017). Briefly, after anesthesia with isoflurane, the brains were isolated and immersed in pre-carbogenated (95% O 2 /5% CO 2 ) ice-cold slicing salt buffer solution (composition in mM: 92 NaCl, 2.5 KCl, 0.5 CaCl 2 •2H 2 O, 10 MgSO 4 , 1.25 NaH 2 PO 4 , 25 glucose, 30 NaHCO 3 , 3 sodium pyruvate, 20 HEPES, titrated to pH 7.4; Pan et al, 2015).…”

Section: Hippocampal Slice Preparationmentioning

confidence: 99%

Direct Medial Entorhinal Cortex Input to Hippocampal CA3 Is Crucial for eEF2K Inhibitor-Induced Neuronal Oscillations in the Mouse Hippocampus

Liu

Peng

Zhuang

et al. 2020

Front. Cell. Neurosci.

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The hippocampal formation plays a vital role in memory formation and takes part in the control of the default neuronal network activity of the brain. It also represents an important structure to analyze drug-induced effects on subregion-specific synchronization of neuronal activity. However, the consequences of an altered functional state of synapses for subregion-specific synchronization of neuronal microcircuits remain to be fully understood. Therefore, we analyzed the direct interaction of neuronal microcircuits utilizing a genetically encoded calcium sensor (GCaMP6s) and local field potential (LFP) recording in acute hippocampal-entorhinal brain slices in response to a modulator of synaptic transmission. We observed that application of the eukaryotic elongation factor-2 kinase (eEF2K) inhibitor A484954, induced a large-scale synchronization of neuronal activity within different regions of the hippocampal formation. This effect was confirmed by the recording of extracellular LFPs. Further, in order to understand if the synchronized activity depended on interconnected hippocampal areas, we lesioned adjacent regions from each other. These experiments identified the origin of A484954-induced synchronized activity in the hippocampal CA3 subfield localized near the hilus of the dentate gyrus. Remarkably, the synchronization of neuronal activity in the hippocampus required an intact connection with the medial entorhinal cortex (MEC). In line with this observation, we detected an increase in neuronal activity in the MEC area after application of A484954. In summary, inhibition of eEF2K alters the intrinsic activity of interconnected neuronal microcircuits dominated by the MEC-CA3 afferents.

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“…In contrast, the longer 3′ UTR acts as a translational suppressor at basal activity levels but as a translational enhancer, via a HuD/PKC-dependent mechanism, when the neuron is active ( Lau et al, 2010 ; Vaghi et al, 2014 ; Vanevski and Xu, 2015 ). Furthermore, translation of transcripts containing the shorter 3′ UTR increases phosphorylation of TrkB, CREB, and other proteins that lead to enhanced synaptic plasticity, and the in vivo consequences of this translation improve both short- and long-term memory formation ( Wang et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

The 3′ UTRs of Brain-Derived Neurotrophic Factor Transcripts Differentially Regulate the Dendritic Arbor

O’Neill

Donohue

Omelchenko

et al. 2018

Front. Cell. Neurosci.

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The patterning of dendrites is regulated by many factors, such as brain-derived neurotrophic factor (BDNF), which our laboratory has previously shown alters the dendritic arbor uniquely depending on the mode of extracellular application. In the current work, we examine how BDNF affects dendritogenesis in hippocampal neurons when it is overexpressed intracellularly by transcripts previously reported to be transported to distinct cellular compartments. The BDNF gene is processed at two different polyadenylation sites, leading to mRNA transcription with two different length 3′ untranslated regions (UTRs), and therefore, different mRNA localization preferences. We found that overexpression of BDNF mRNA with or without 3′ UTRs significantly alters dendritic branching compared to branching in control neurons as analyzed by Sholl distribution curves. Unexpectedly, we found that the overexpression of the shorter BDNF mRNA (reported to be preferentially targeted to the cell body) results in similar changes to Sholl curves compared to overexpression of the longer BDNF mRNA (reported to be preferentially targeted to both the cell body and dendrites). We also investigated whether the BDNF receptor TrkB mediates these changes and found that inhibiting TrkB blocks increases in Sholl curves, although at different distances depending on the transcript’s UTR. Finally, although it is not found in nature, we also examined the effects of overexpressing BDNF mRNA with the unique portion of the longer 3′ UTR since it was previously shown to be necessary for dendritic targeting of mRNA. We found that its overexpression increases Sholl curves at distances close to the cell body and that these changes also depend on TrkB activity. This work illustrates how the mRNA spatial code affects how BDNF alters local dendritogenesis and how TrkB may mediate these effects. Finally, our findings emphasize the importance of intracellular transport of BDNF mRNAs in the regulation of dendrite morphology.

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Translation of BDNF-gene transcripts with short 3′ UTR in hippocampal CA1 neurons improves memory formation and enhances synaptic plasticity-relevant signaling pathways

Cited by 15 publications

References 81 publications

Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus

Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus

Direct Medial Entorhinal Cortex Input to Hippocampal CA3 Is Crucial for eEF2K Inhibitor-Induced Neuronal Oscillations in the Mouse Hippocampus

The 3′ UTRs of Brain-Derived Neurotrophic Factor Transcripts Differentially Regulate the Dendritic Arbor

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