scholarly journals Synaptic plasticity is altered by treatment with pharmacological levels of retinoic acid acting nongenomically however endogenous retinoic acid has not been shown to control synaptic plasticity

2021 ◽  
Author(s):  
Gregg Duester
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Granule Cells ◽  
Neurological Diseases ◽  
Active Form ◽  
Adult Brain ◽  
Loss Of Function ◽  
Regulate Gene Expression ◽  
Nongenomic Effects ◽  
Regulate Gene

A paper recently published by eLife on forebrain cortical synaptic plasticity reports that retinoic acid (RA) alters synaptopodin-dependent metaplasticity in mouse dentate granule cells (Lenz et al., 2021). RA is the active form of vitamin A that functions as a ligand for nuclear RA receptors that directly bind genomic control regions to regulate gene expression (Chambon, 1996; Ghyselinck and Duester, 2019). However, some studies have suggested that RA may have nongenomic effects outside of the nucleus, particularly with regard to synaptic plasticity (Aoto et al., 2008; Zhang et al., 2018). The current results reported by Lenz et al. demonstrate that treatment with pharmacological levels of RA can alter synaptic plasticity which may be useful to treat neurological diseases (Lenz et al., 2021). However, the results reported here and those reported by others have not shown that endogenous RA is normally required for synaptic plasticity (or any other nongenomic effect) as there are no reports of genetic loss-of-function studies that remove endogenous RA in adult brain. The implication is that pharmacological levels of RA result in nongenomic effects, some of which may be helpful to treat certain diseases but in other cases this may cause unwanted side-effects.

scholarly journals Synaptic Plasticity is Altered by Supraphysiological Levels of Retinoic Acid Acting Nongenomically however Endogenous Retinoic Acid Has Not Been Shown to Control Synaptic Plasticity

2021 ◽  
Author(s):  
Gregg Duester
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Vitamin A ◽  
Granule Cells ◽  
Dorsal Hippocampus ◽  
Active Form ◽  
Loss Of Function ◽  
Regulate Gene Expression ◽  
Regulate Gene

A paper recently published on forebrain cortical synaptic plasticity reports that retinoic acid (RA) induces synaptopodin-dependent metaplasticity in mouse dentate granule cells (Lenz et al., 2021). Retinoic acid (RA) is the active form of vitamin A that functions as a ligand for nuclear RA receptors that directly bind genomic control regions to regulate gene expression (Chambon, 1996; Ghyselinck and Duester, 2019). However, Lenz et al. report that RA functions in a nongenomic fashion to control forebrain cortical synaptic plasticity which modulates synaptic transmission to effectively respond to specific stimuli; specifically, they report that this nongenomic response occurs in the dorsal hippocampus but not ventral hippocampus. They performed RA treatment studies which provided information on how a supraphysiological level of RA effects synaptic plasticity. However, the authors did not perform an RA loss-of-function study to verify that endogenous RA is required for synaptic plasticity.

scholarly journals Loss of miR-210 leads to progressive retinal degeneration in Drosophila melanogaster

2019 ◽  
Vol 2 (1) ◽  
pp. e201800149 ◽  
Author(s):  
Carina M Weigelt ◽  
Oliver Hahn ◽  
Katharina Arlt ◽  
Matthias Gruhn ◽  
Annika J Jahn ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Small Rna ◽  
Fat Body ◽  
Photoreceptor Cells ◽  
Adult Brain ◽  
Small Rna Sequencing ◽  
Regulate Gene Expression ◽  
Knockout Mutants ◽  
Non Coding Rnas ◽  
Regulate Gene

miRNAs are small, non-coding RNAs that regulate gene expression post-transcriptionally. We used small RNA sequencing to identify tissue-specific miRNAs in the adult brain, thorax, gut, and fat body of Drosophila melanogaster. One of the most brain-specific miRNAs that we identified was miR-210, an evolutionarily highly conserved miRNA implicated in the regulation of hypoxia in mammals. In Drosophila, we show that miR-210 is specifically expressed in sensory organs, including photoreceptors. miR-210 knockout mutants are not sensitive toward hypoxia but show progressive degradation of photoreceptor cells, accompanied by decreased photoreceptor potential, demonstrating an important function of miR-210 in photoreceptor maintenance and survival.

scholarly journals mir124-dependent tagging of glutamatergic synapses by synaptopodin controls non-uniform and input-specific homeostatic synaptic plasticity

2021 ◽  
Author(s):  
Sandra Dubes ◽  
Anais Soula ◽  
Sebastien Benquet ◽  
Beatrice Tessier ◽  
Christel Poujol ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Specific Activity ◽  
Neurological Diseases ◽  
Loss Of Function ◽  
Glutamatergic Synapses ◽  
Homeostatic Synaptic Plasticity ◽  
Hebbian Plasticity ◽  
Molecular Determinants ◽  
Spine Apparatus ◽  
Local Expression

Homeostatic synaptic plasticity (HSP) is a process by which neurons adjust synaptic strengths to compensate for various perturbations and which allows to stabilize neuronal activity. Yet, whether the highly diverse synapses harboring a neuron respond uniformly to a same perturbation is unclear and the underlying molecular determinants remain to be identified. Here, using patch-clamp recordings, immunolabeling and imaging approaches, we report that the ability of individual synapses to undergo HSP in response to activity-deprivation paradigms depends on the local expression of the spine apparatus related protein synaptopodin (SP) acting as a synaptic tag to promote AMPA receptor synaptic accumulation and spine growth. Gain and loss-of-function experiments indicate that this process relies on the local de-repression of SP translation by miR124 which supports both non-uniform and synapse-autonomous HSP induced by global or input-specific activity deprivation, respectively. Our findings uncover an unexpected synaptic-tagging mechanism for HSP, whose molecular actors are intriguingly shared with Hebbian plasticity and linked to multiple neurological diseases.

scholarly journals All-trans retinoic acid induces synaptopodin-dependent metaplasticity in mouse dentate granule cells

2021 ◽  
Author(s):  
Maximilian Lenz ◽  
Amelie Eichler ◽  
Pia Kruse ◽  
Julia Muellerleile ◽  
Thomas Deller ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Brain Region ◽  
Granule Cells ◽  
Atra Treatment ◽  
Dentate Granule Cells ◽  
Inhibitory Neurotransmission ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

The vitamin A derivative all-trans retinoic acid (atRA) is a key mediator of synaptic plasticity. Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. However, it remains unclear how atRA mediates brain region-specific effects on synaptic transmission and plasticity. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult male C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata. In contrast to what has been reported in other brain regions, no major changes in synaptic transmission were observed in the ventral and dorsal hippocampus 6 hours after atRA administration. Likewise, no evidence for changes in the intrinsic properties of hippocampal dentate granule cells was obtained in the atRA-treated group. Moreover, hippocampal transcriptome analysis revealed no essential changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, i.e., for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic transmission. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, thus extending our previous results on the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.

scholarly journals The Snail transcription factor CES-1 regulates glutamatergic behavior in C. elegans

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245587
Author(s):  
Lidia Park ◽  
Eric S. Luth ◽  
Kelsey Jones ◽  
Julia Hofer ◽  
Irene Nguyen ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Active Form ◽  
Cell Lineage ◽  
Receptor Expression ◽  
Loss Of Function ◽  
Major Mechanism

Regulation of AMPA-type glutamate receptor (AMPAR) expression and function alters synaptic strength and is a major mechanism underlying synaptic plasticity. Although transcription is required for some forms of synaptic plasticity, the transcription factors that regulate AMPA receptor expression and signaling are incompletely understood. Here, we identify the Snail family transcription factor ces-1 in an RNAi screen for conserved transcription factors that regulate glutamatergic behavior in C. elegans. ces-1 was originally discovered as a selective cell death regulator of neuro-secretory motor neuron (NSM) and I2 interneuron sister cells in C. elegans, and has almost exclusively been studied in the NSM cell lineage. We found that ces-1 loss-of-function mutants have defects in two glutamatergic behaviors dependent on the C. elegans AMPA receptor GLR-1, the mechanosensory nose-touch response and spontaneous locomotion reversals. In contrast, ces-1 gain-of-function mutants exhibit increased spontaneous reversals, and these are dependent on glr-1 consistent with these genes acting in the same pathway. ces-1 mutants have wild type cholinergic neuromuscular junction function, suggesting that they do not have a general defect in synaptic transmission or muscle function. The effect of ces-1 mutation on glutamatergic behaviors is not due to ectopic cell death of ASH sensory neurons or GLR-1-expressing neurons that mediate one or both of these behaviors, nor due to an indirect effect on NSM sister cell deaths. Rescue experiments suggest that ces-1 may act, in part, in GLR-1-expressing neurons to regulate glutamatergic behaviors. Interestingly, ces-1 mutants suppress the increased reversal frequencies stimulated by a constitutively-active form of GLR-1. However, expression of glr-1 mRNA or GFP-tagged GLR-1 was not decreased in ces-1 mutants suggesting that ces-1 likely promotes GLR-1 function. This study identifies a novel role for ces-1 in regulating glutamatergic behavior that appears to be independent of its canonical role in regulating cell death in the NSM cell lineage.

scholarly journals An old weapon with a new function: PIWI-interacting RNAs in neurodegenerative diseases

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiaobing Huang ◽  
Garry Wong
Keyword(s):  
Neurodegenerative Diseases ◽  
Genome Stability ◽  
Neurological Diseases ◽  
Recent Decade ◽  
Regulate Gene Expression ◽  
Therapeutic Practice ◽  
C Elegans ◽  
Harmful Effects ◽  
Maintain Genome Stability ◽  
Regulate Gene

AbstractPIWI-interacting RNAs (piRNAs) are small non-coding transcripts that are highly conserved across species and regulate gene expression through pre- and post-transcriptional processes. piRNAs were originally discovered in germline cells and protect against transposable element expression to promote and maintain genome stability. In the recent decade, emerging roles of piRNAs have been revealed, including the roles in sterility, tumorigenesis, metabolic homeostasis, neurodevelopment, and neurodegenerative diseases. In this review, we summarize piRNA biogenesis in C. elegans, Drosophila, and mice, and further elaborate upon how piRNAs mitigate the harmful effects of transposons. Lastly, the most recent findings on piRNA participation in neurological diseases are highlighted. We speculate on the mechanisms of piRNA action in the development and progression of neurodegenerative diseases. Understanding the roles of piRNAs in neurological diseases may facilitate their applications in diagnostic and therapeutic practice.

scholarly journals CircFOXK2 Promotes Tumor Growth and Metastasis of Pancreatic Ductal Adenocarcinoma via Complexing with RNA Binding Proteins and Sponging MiR-942

2019 ◽  
Author(s):  
Chi Hin Wong ◽  
Ut Kei Lou ◽  
Youjia Li ◽  
Stephen Lam Chan ◽  
Joanna Hung-Man Tong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
List Type ◽  
Interacting Proteins ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Regulate Gene Expression ◽  
Regulate Gene

AbstractObjectiveCircular RNA (circRNA) is a novel class of non-coding RNAs that regulate gene expression. However, the role of circRNAs in pancreatic ductal adenocarcinoma (PDAC) is largely unknown.DesignWe performed circRNA sequencing of non-tumor HPDE and PDAC cells. We investigated the functions of circFOXK2 in PDAC by gain-of-function and loss-of-function assays. Bioinformatics analysis, luciferase assay and microRNA pulldown assays were performed to identify circFOXK2 interacting-miRNAs. To further investigate the mechanism, we performed circRNA-pulldown and mass spectrometry to identify circFOXK2-interacting proteins in PDAC.ResultsWe identified 169 differentially expressed circRNAs in PDAC cells. We validated that one of the circRNAs circFOXK2 was significantly up-regulated in PDAC cells and in 63 % of primary tumor (53 out of 84). Gain-of-function and loss-of-function assays demonstrated that circFOXK2 promoted PDAC cell growth, migration and invasion. CircFOXK2 was also involved in cell cycle progression and apoptosis. circFOXK2 functioned as sponge for miR-942, and in turn promoted the expression of miR-942 targets ANK1, GDNF and PAX6. Furthermore, circFOXK2 interacted with 94 proteins, which were involved in cell adhesion and mRNA splicing. Among these circFOXK2-interacting proteins, YBX1 and hnRNPK were validated by RNA immunoprecipitation. Importantly, circFOKX2 interacted with YBX1 and hnRNPK targets NUF2 and PDXK in PDAC cells. Knockdown of circFOXK2 reduced the binding of YBX1 and hnRNPK to NUF2 and PDXK, and in turn decreased their expressions in PDAC cells.ConclusionWe identified that circFOXK2 promoted PDAC cells growth and metastasis. Also, circFOXK2 complexed with YBX1 and hnRNPK to promote the expressions of oncogenic proteins.Significance of this studyWhat is already known on this subject?Differentially expressed circRNAs are involved in carcinogenesis of many cancers.CircRNAs function as microRNA sponges to regulate gene expression.The roles of circRNAs in PDAC progression is largely unknown.What are the new findings?circFOXK2 is upregulated in PDAC primary tumors.circFOXK2 promotes PDAC tumor growth and liver metastasis.circFOXK2 functions as sponges for miR-942 to promote the expressions of oncogenic ANK1, GDNF and PAX6.circFOXK2 complexes with YBX1 and hnRNPK to promote the expressions of oncogenic proteins in PDAC.How might it impact on clinical practice in the foreseeable future?circFOXK2 upregulation in PDAC may function as a novel biomarker for diagnosis.circFOXK2 may be a novel therapeutic target in treating PDAC.

scholarly journals All-trans retinoic acid induces synaptopodin-dependent metaplasticity in mouse dentate granule cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Maximilian Lenz ◽  
Amelie Eichler ◽  
Pia Kruse ◽  
Julia Muellerleile ◽  
Thomas Deller ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Brain Region ◽  
Granule Cells ◽  
Long Term Potentiation ◽  
Atra Treatment ◽  
Dentate Granule Cells ◽  
Inhibitory Neurotransmission ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Previously we showed that the vitamin A metabolite all-trans retinoic acid (atRA) induces synaptic plasticity in acute brain slices prepared from the mouse and human neocortex (Lenz et al., 2021). Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata—a brain region implicated in memory acquisition. No major changes in synaptic transmission were observed in the ventral hippocampus while a significant increase in both spontaneous excitatory postsynaptic current frequencies and synapse numbers were evident in the dorsal hippocampus 6 hr after atRA administration. The intrinsic properties of hippocampal dentate granule cells were not significantly different and hippocampal transcriptome analysis revealed no essential neuronal changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, that is, for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic strength. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, therefore, extending our previous results regarding the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.

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