scholarly journals REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Cosimo Prestigio ◽  
Daniele Ferrante ◽  
Antonella Marte ◽  
Alessandra Romei ◽  
Gabriele Lignani ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Homeostatic Plasticity ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Transcriptional Responses ◽  
Neuronal Homeostasis ◽  
Receptor Inhibition ◽  
Sequential Activation ◽  
Complex Target

The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron-specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation, triggers a homeostatic rearrangement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs in mouse cultured hippocampal neurons. Notably, this effect is limited to inhibitory-onto-excitatory neuron synapses, whose density increases at somatic level and decreases in dendritic regions, demonstrating a complex target- and area-selectivity. The upscaling of perisomatic inhibition was occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and Bdnf gene programs. On the opposite, the downscaling of dendritic inhibition was REST-dependent, but BDNF-independent. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at rescuing physiological levels of network activity in front of the ever-changing environment.

scholarly journals REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion

2021 ◽  
Author(s):  
Cosimo Prestigio ◽  
Daniele Ferrante ◽  
Antonella Marte ◽  
Alessandra Romei ◽  
Gabriele Lignani ◽  
...  
Keyword(s):  
Homeostatic Plasticity ◽  
Inhibitory Synapses ◽  
Glutamatergic Transmission ◽  
Transcriptional Responses ◽  
Gabaergic Transmission ◽  
Neuronal Homeostasis ◽  
Receptor Inhibition ◽  
Sequential Activation ◽  
Repressor Element

ABSTRACTThe repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation triggers a homeostatic enhancement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs. Notably, this effect was only observed at inhibitory-onto-excitatory neuron synapses, whose density increased at perisomatic sites, demonstrating a strict target-selectivity. These effects were occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and BDNF gene programs. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at preserving physiological levels of neuronal activity in front of the ever-changing environment.Impact StatementThis work elucidates the mechanisms by which the transcriptional regulator REST/NRSF selectively upregulates GABAergic transmission onto excitatory neurons in response to hyperactivity to rescue neuronal homeostasis.

scholarly journals A metaplasticity view of the interaction between homeostatic and Hebbian plasticity

2017 ◽  
Vol 372 (1715) ◽  
pp. 20160155 ◽  
Author(s):  
Ada X. Yee ◽  
Yu-Tien Hsu ◽  
Lu Chen
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Associative Learning ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Homeostatic Plasticity ◽  
Network Activity ◽  
Mammalian Central Nervous System ◽  
Hebbian Plasticity

Hebbian and homeostatic plasticity are two major forms of plasticity in the nervous system: Hebbian plasticity provides a synaptic basis for associative learning, whereas homeostatic plasticity serves to stabilize network activity. While achieving seemingly very different goals, these two types of plasticity interact functionally through overlapping elements in their respective mechanisms. Here, we review studies conducted in the mammalian central nervous system, summarize known circuit and molecular mechanisms of homeostatic plasticity, and compare these mechanisms with those that mediate Hebbian plasticity. We end with a discussion of ‘local’ homeostatic plasticity and the potential role of local homeostatic plasticity as a form of metaplasticity that modulates a neuron's future capacity for Hebbian plasticity. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.

Disruption of Coherent Oscillations in Inhibitory Networks With Anesthetics: Role of GABAA Receptor Desensitization

2002 ◽  
Vol 88 (5) ◽  
pp. 2821-2833 ◽  
Author(s):  
Pamela M. Baker ◽  
Peter S. Pennefather ◽  
Beverley A. Orser ◽  
Frances K. Skinner
Keyword(s):  
Network Activity ◽  
Oscillatory Activity ◽  
Inhibitory Synapses ◽  
Receptor Desensitization ◽  
Anesthetic Drugs ◽  
Detailed Kinetic Model ◽  
Central Synapses ◽  
Kinetics Of ◽  
Inhibitory Networks

The effect of anesthetic drugs at central synapses can be described quantitatively by developing kinetic models of ligand-gated ion channels. Experiments have shown that the hypnotic propofol and the sedative benzodiazepine midazolam have similar effects on single inhibitory postsynaptic potentials (IPSPs) but very different effects on slow desensitization that are not revealed by examining single responses. Synchronous oscillatory activity in networks of interneurons connected by inhibitory synapses has been implicated in many hippocampal functions, and differences in the kinetics of the GABAergic response observed with anesthetics can affect this activity. Thus we have examined the effect of propofol and midazolam-enhanced IPSPs using mathematical models of self-inhibited one- and two-cell inhibitory networks. A detailed kinetic model of the GABAA channel incorporating receptor desensitization is used at synapses in our models. The most dramatic effect of propofol is the modulation of slow desensitization. This is only revealed when the network is driven at frequencies that are thought to be relevant to cognitive tasks performed in the hippocampus. The level of desensitization at synapses with propofol is significantly reduced compared to control synapses. In contrast, midazolam increases macroscopic desensitization at network synapses by altering receptor affinity without concurrently modifying desensitization rates. These differences in gating between the two drugs are shown to alter network activity in stereotypically different ways. Specifically, propofol dramatically increases the amount of excitatory drive necessary for synchronized behavior relative to control, which is not the case for midazolam. Moreover, the range of parameters for which synchrony occurs is larger for propofol but smaller for midazolam, relative to control. This is an important first step in linking alterations in channel kinetics with behavioral changes.

Endocannabinoid system in the neurodevelopment of GABAergic interneurons: implications for neurological and psychiatric disorders

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Chang-geng Song ◽  
Xin Kang ◽  
Fang Yang ◽  
Wan-qing Du ◽  
Jia-jia Zhang ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Network Activity ◽  
Inhibitory Neurons ◽  
Gabaergic Interneurons ◽  
Neural Stem Progenitor Cells ◽  
The Central Nervous System ◽  
Interneuron Development

Abstract In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.

The role of GABAA receptor biogenesis, structure and function in epilepsy

2006 ◽  
Vol 34 (5) ◽  
pp. 863-867 ◽  
Author(s):  
S. Mizielinska ◽  
S. Greenwood ◽  
C.N. Connolly
Keyword(s):  
Gabaa Receptor ◽  
Structure And Function ◽  
Inhibitory Synapses ◽  
Normal Brain ◽  
Synaptic Targeting ◽  
Acid Type ◽  
Normal Brain Function ◽  
And Function ◽  
The Brain

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.

scholarly journals Downregulation of miR-383 reduces depression-like behavior through targeting Wnt family member 2 (Wnt2) in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shanshan Liu ◽  
Qing Liu ◽  
Yanjie Ju ◽  
Lei Liu
Keyword(s):  
Inflammatory Response ◽  
Family Member ◽  
Chronic Stress ◽  
Hippocampal Neurons ◽  
Luciferase Reporter ◽  
Mild Stress ◽  
Neural Injury ◽  
Expression Levels ◽  
Qrt Pcr

AbstractThis study aimed to evaluate the role of miR-383 in the regulation of Wnt-2 signaling in the rat model of chronic stress. The male SD rats with depressive-like behaviors were stimulated with chronic unpredictable mild stress (CUMS) including ice-water swimming for 5 min, food deprivation for 24 h, water deprivation for 24 h, stimulating tail for 1 min, turning night into day, shaking for 15 min (once/s), and wrap restraint (5 min/time) every day for 21 days. The expression levels of miRNAs were detected by qRT-PCR, and the expression levels of Wnt2, depression-impacted proteins (GFAP, BDNF, CREB), brain neurotransmitters (5-HT, NE, DA) and apoptosis-related proteins (Bax and Bcl-2) were evaluated by qRT-PCR and western blot. Bioinformatic analysis and luciferase reporter assay were performed to determine the relationship between miR-383 and Wnt2. Ethological analysis was evaluated by sugar preference test, refuge island test and open field tests. Rescue experiments including knockdown of miR-383, overexpression and silencing of Wnt2 were performed to determine the role of miR-383. High expression levels of miR-383 were observed in the hippocampus of rats submitted to CUMS model. Downregulation of miR-383 significantly inhibited the apoptosis and inflammatory response of hippocampal neurons, and increased the expression levels of GFAP, BDNF and CREB which were impacted in depression, as well as neurotransmitters, then attenuated neural injury in rats induced by CUMS. Furthermore, Wnt family member 2 (Wnt2) was identified as a target of miR-383, and silencing of Wnt2 obviously attenuated the protective effect of miR-383 inhibitor on the apoptosis and inflammatory response in hippocampal neurons, as well as neural injury in CUMS-induced rats. Downregulation of miR-383 ameliorated the behavioral and neurochemical changes induced by chronic stress in rats by directly targeting Wnt2, indicating that the miR-383/Wnt2 axis might be a potential therapeutic target for MDD.

scholarly journals Deletion of the Actin-Associated Tropomyosin Tpm3 Leads to Reduced Cell Complexity in Cultured Hippocampal Neurons—New Insights into the Role of the C-Terminal Region of Tpm3.1

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 715
Author(s):  
Tamara Tomanić ◽  
Claire Martin ◽  
Holly Stefen ◽  
Esmeralda Parić ◽  
Peter Gunning ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Growth Cones ◽  
Amino Acid Residues ◽  
Terminal Amino Acid ◽  
C Terminus ◽  
Primary Mouse ◽  
Terminal Amino

Tropomyosins (Tpms) have been described as master regulators of actin, with Tpm3 products shown to be involved in early developmental processes, and the Tpm3 isoform Tpm3.1 controlling changes in the size of neuronal growth cones and neurite growth. Here, we used primary mouse hippocampal neurons of C57/Bl6 wild type and Bl6Tpm3flox transgenic mice to carry out morphometric analyses in response to the absence of Tpm3 products, as well as to investigate the effect of C-terminal truncation on the ability of Tpm3.1 to modulate neuronal morphogenesis. We found that the knock-out of Tpm3 leads to decreased neurite length and complexity, and that the deletion of two amino acid residues at the C-terminus of Tpm3.1 leads to more detrimental changes in neurite morphology than the deletion of six amino acid residues. We also found that Tpm3.1 that lacks the 6 C-terminal amino acid residues does not associate with stress fibres, does not segregate to the tips of neurites, and does not impact the amount of the filamentous actin pool at the axonal growth cones, as opposed to Tpm3.1, which lacks the two C-terminal amino acid residues. Our study provides further insight into the role of both Tpm3 products and the C-terminus of Tpm3.1, and it forms the basis for future studies that aim to identify the molecular mechanisms underlying Tpm3.1 targeting to different subcellular compartments.

The role of chloride transport in postsynaptic inhibition of hippocampal neurons

Science ◽  
1986 ◽  
Vol 232 (4756) ◽  
pp. 1413-1415 ◽  
Author(s):  
U Misgeld ◽  
R. Deisz ◽  
H. Dodt ◽  
H. Lux
Keyword(s):  
Hippocampal Neurons ◽  
Chloride Transport ◽  
Postsynaptic Inhibition

scholarly journals Assessment of the Role of Activator Protein-1 on Transcription of the Mouse Steroidogenic Acute Regulatory Protein Gene

2004 ◽  
Vol 18 (3) ◽  
pp. 558-573 ◽  
Author(s):  
Pulak R. Manna ◽  
Darrell W. Eubank ◽  
Douglas M. Stocco
Keyword(s):  
Binding Site ◽  
Gene Transcription ◽  
Dna Sequences ◽  
Regulatory Protein ◽  
Activator Protein 1 ◽  
Transcriptional Responses ◽  
Activator Protein ◽  
Steroidogenic Acute Regulatory ◽  
Star Gene

Abstract cAMP-dependent mechanisms regulate the steroidogenic acute regulatory (StAR) protein even though its promoter lacks a consensus cAMP response-element (CRE, TGACGTCA). Transcriptional regulation of the StAR gene has been demonstrated to involve combinations of DNA sequences that provide recognition motifs for sequence-specific transcription factors. We recently identified and characterized three canonical 5′-CRE half-sites within the cAMP-responsive region (−151/−1 bp) of the mouse StAR gene. Among these CRE elements, the CRE2 half-site is analogous (TGACTGA) to an activator protein-1 (AP-1) sequence [TGA(C/G)TCA]; therefore, the role of the AP-1 transcription factor was explored in StAR gene transcription. Mutation in the AP-1 element demonstrated an approximately 50% decrease in StAR reporter activity. Using EMSA, oligonucleotide probes containing an AP-1 binding site were found to specifically bind to nuclear proteins obtained from mouse MA-10 Leydig and Y-1 adrenocortical tumor cells. The integrity of the sequence-specific AP-1 element in StAR gene transcription was assessed using the AP-1 family members, Fos (c-Fos, Fra-1, Fra-2, and Fos B) and Jun (c-Jun, Jun B, and Jun D), which demonstrated the involvement of Fos and Jun in StAR gene transcription to varying degrees. Disruption of the AP-1 binding site reversed the transcriptional responses seen with Fos and Jun. EMSA studies utilizing antibodies specific to Fos and Jun demonstrated the involvement of several AP-1 family proteins. Functional assessment of Fos and Jun was further demonstrated by transfecting antisense c-Fos, Fra-1, and dominant negative forms of Fos (A-Fos) and c-Jun (TAM-67) into MA-10 cells, which significantly (P < 0.01) repressed transcription of the StAR gene. Mutation of the AP-1 site in combination with mutations in other cis-elements resulted in a further decrease of StAR promoter activity, demonstrating a functional cooperation between these factors. Mammalian two-hybrid assays revealed high-affinity protein-protein interactions between c-Fos and c-Jun with steroidogenic factor 1, GATA-4, and CCAAT/enhancer binding protein-β. These findings demonstrate that Fos and Jun can bind to the TGACTGA element in the StAR promoter and provide novel insights into the mechanisms regulating StAR gene transcription.

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