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

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.

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

eLife ◽

10.7554/elife.69058 ◽

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.

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

Biochemical Society Transactions ◽

10.1042/bst0340863 ◽

2006 ◽

Vol 34 (5) ◽

pp. 863-867 ◽

Cited By ~ 14

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.

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Development-Dependent Plasticity in Vasoactive Intestinal Polypeptide Neurons in the Infralimbic Cortex

Cerebral Cortex Communications ◽

10.1093/texcom/tgab007 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Stuart A Collins ◽

Ipe Ninan

Keyword(s):

Sex Differences ◽

Anxiety Disorders ◽

Vasoactive Intestinal Polypeptide ◽

Cortical Plasticity ◽

Male Mice ◽

Infralimbic Cortex ◽

Membrane Excitability ◽

Gabaergic Transmission ◽

Intestinal Polypeptide

Abstract The onset of several neuropsychiatric disorders including anxiety disorders coincides with adolescence. Consistently, threat extinction, which plays a key role in the regulation of anxiety-related behaviors, is diminished during adolescence. Furthermore, this attenuated threat extinction during adolescence is associated with an altered synaptic plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for threat extinction. However, the mechanism underlying the altered plasticity in the IL-mPFC during adolescence is unclear. Given the purported role of vasoactive intestinal polypeptide expressing interneurons (VIPINs) in disinhibition and hence their potential to affect cortical plasticity, we examined whether VIPINs exhibit an adolescence-specific plasticity in the IL-mPFC. We observed an increase in GABAergic transmission and a decrease in excitability in VIPINs during adolescence. Male mice show a significantly higher VIPIN-pyramidal neuron GABAergic transmission compared with female mice. The observed increase in GABAergic transmission and a decrease in membrane excitability in VIPINs during adolescence could play a role in the altered plasticity in the adolescent IL-mPFC. Furthermore, the suppression of VIPIN-mediated GABAergic transmission in females might be relevant to sex differences in anxiety disorders.

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

Molecular Endocrinology ◽

10.1210/me.2003-0223 ◽

2004 ◽

Vol 18 (3) ◽

pp. 558-573 ◽

Cited By ~ 52

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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Transcription Factors Pcr1 and Atf1 Have Distinct Roles in Stress- and Sty1-Dependent Gene Regulation

Eukaryotic Cell ◽

10.1128/ec.00465-07 ◽

2008 ◽

Vol 7 (5) ◽

pp. 826-835 ◽

Cited By ~ 52

Author(s):

Miriam Sansó ◽

Madelaine Gogol ◽

José Ayté ◽

Chris Seidel ◽

Elena Hidalgo

Keyword(s):

Mitogen Activated Protein Kinase ◽

Transcriptional Responses ◽

Repressive Effect ◽

Mitogen Activated Protein ◽

Promote Cell Survival ◽

Stress Dependent ◽

Microarray Analyses ◽

Stress Activation

ABSTRACT The mitogen-activated protein kinase Sty1 is essential for the regulation of transcriptional responses that promote cell survival in response to different types of environmental stimuli in Schizosaccharomyces pombe. Upon stress activation, Sty1 reversibly accumulates in the nucleus, where it stimulates gene expression via the Atf1 transcription factor. The Atf1 protein forms a heterodimer with Pcr1, but the specific role of this association is controversial. We have carried out a comparative analysis of strains lacking these proteins individually. We demonstrate that Atf1 and Pcr1 have similar but not identical roles in S. pombe, since cells lacking Pcr1 do not share all the phenotypes reported for Δatf1 cells. Northern blot and microarray analyses demonstrate that the responses to specific stresses of cells lacking either Pcr1 or Atf1 do not fully overlap, and even though most Atf1-dependent genes induced by osmotic stress are also Pcr1 dependent, a subset of genes require only the presence of Atf1 for their induction. Whereas binding of Atf1 to most stress-dependent genes requires the presence of Pcr1, we demonstrate here that Atf1 can bind to the Pcr1-independent promoters in a Δpcr1 strain in vivo. Furthermore, these analyses show that both proteins have a global repressive effect on stress-dependent and stress-independent genes.

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AMPA receptor inhibition by synaptically released zinc

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512296112 ◽

2015 ◽

Vol 112 (51) ◽

pp. 15749-15754 ◽

Cited By ~ 54

Author(s):

Bopanna I. Kalappa ◽

Charles T. Anderson ◽

Jacob M. Goldberg ◽

Stephen J. Lippard ◽

Thanos Tzounopoulos

Keyword(s):

Dorsal Cochlear Nucleus ◽

Fine Tuning ◽

Receptor Inhibition ◽

Endogenous Modulator ◽

Excitatory Neurotransmission ◽

Zinc Levels ◽

Zinc Inhibition ◽

Endogenous Modulators ◽

Activity Dependent

The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.

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GABA release selectively regulates synapse development at distinct inputs on direction-selective retinal ganglion cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1803490115 ◽

2018 ◽

Vol 115 (51) ◽

pp. E12083-E12090 ◽

Cited By ~ 5

Author(s):

Adam Bleckert ◽

Chi Zhang ◽

Maxwell H. Turner ◽

David Koren ◽

David M. Berson ◽

...

Keyword(s):

Ganglion Cells ◽

Selective Reduction ◽

Amacrine Cells ◽

Gaba Release ◽

Direction Selectivity ◽

Inhibitory Synapses ◽

Retinal Ganglion ◽

Gabaergic Transmission ◽

Starburst Amacrine Cells ◽

Receptor Clusters

Synaptic inhibition controls a neuron’s output via functionally distinct inputs at two subcellular compartments, the cell body and the dendrites. It is unclear whether the assembly of these distinct inhibitory inputs can be regulated independently by neurotransmission. In the mammalian retina, γ-aminobutyric acid (GABA) release from starburst amacrine cells (SACs) onto the dendrites of on–off direction-selective ganglion cells (ooDSGCs) is essential for directionally selective responses. We found that ooDSGCs also receive GABAergic input on their somata from other amacrine cells (ACs), including ACs containing the vasoactive intestinal peptide (VIP). When net GABAergic transmission is reduced, somatic, but not dendritic, GABAA receptor clusters on the ooDSGC increased in number and size. Correlative fluorescence imaging and serial electron microscopy revealed that these enlarged somatic receptor clusters are localized to synapses. By contrast, selectively blocking vesicular GABA release from either SACs or VIP ACs did not alter dendritic or somatic receptor distributions on the ooDSGCs, showing that neither SAC nor VIP AC GABA release alone is required for the development of inhibitory synapses in ooDSGCs. Furthermore, a reduction in net GABAergic transmission, but not a selective reduction from SACs, increased excitatory drive onto ooDSGCs. This increased excitation may drive a homeostatic increase in ooDSGC somatic GABAA receptors. Differential regulation of GABAA receptors on the ooDSGC’s soma and dendrites could facilitate homeostatic control of the ooDSGC’s output while enabling the assembly of the GABAergic connectivity underlying direction selectivity to be indifferent to altered transmission.

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Aβ-Induced Repressor Element 1-Silencing Transcription Factor (REST) Gene Delivery Suppresses Activation of Microglia-Like BV-2 Cells

Neural Plasticity ◽

10.1155/2020/8888871 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Tongya Yu ◽

Hui Quan ◽

Yuzhen Xu ◽

Yunxiao Dou ◽

Feihong Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Proliferation ◽

Transcription Factor ◽

Cell Activation ◽

Type I ◽

Hairpin Rna ◽

Cell Dysfunction ◽

Repressor Element

Compelling evidence from basic molecular biology has demonstrated the crucial role of microglia in the pathogenesis of Alzheimer’s disease (AD). Microglia were believed to play a dual role in both promoting and inhibiting Alzheimer’s disease progression. It is of great significance to regulate the function of microglia and make them develop in a favorable way. In the present study, we investigated the function of repressor element 1-silencing transcription factor (REST) in Aβ1-42-induced BV-2 cell dysfunction. We concluded that Aβ1-42 could promote type I activation of BV-2 cells and induce cell proliferation, migration, and proinflammation cytokine TNF-α, IL-1β, and IL-6 expression. Meanwhile, REST was upregulated, and nuclear translocalization took place due to Aβ1-42 stimulation. When REST was knocked down by a specific short hairpin RNA (sh-RNA), BV-2 cell proliferation, migration, and proinflammation cytokine expression and secretion induced by Aβ1-42 were increased, demonstrating that REST may act as a repressor of microglia-like BV-2 cell activation.

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Calretinin expression in the mammalian neocortex: a review

Physiological Research ◽

10.33549/physiolres.931930 ◽

2010 ◽

pp. 665-677

Author(s):

F Barinka ◽

R Druga

Keyword(s):

Calcium Binding ◽

Binding Protein ◽

Calcium Binding Protein ◽

Actual Knowledge ◽

Neuronal Homeostasis ◽

Physiological Properties ◽

Cortical Interneurons

In the mammalian neocortex, the calcium-binding protein calretinin is expressed in a subset of cortical interneurons. In the recent years, research on interneurons is one of the most rapidly growing fields in neuroscience. This review summarizes the actual knowledge of the functions of calretinin in neuronal homeostasis and particularly of the distribution, connectivity and physiological properties of calretinin expressing interneurons in the neocortex of rodents and primates, including humans. The possible neuroprotective role of calretinin and the presumed “resistance” of calretinin-expressing interneurons to various pathological processes are also discussed.

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Paracrine interactions between epithelial cells promote colon cancer growth

10.1101/2020.12.16.423051 ◽

2020 ◽

Author(s):

Guillaume Jacquemin ◽

Annabelle Wurmser ◽

Mathilde Huyghe ◽

Wenjie Sun ◽

Meghan Perkins ◽

...

Keyword(s):

Epithelial Cells ◽

Cancer Cells ◽

Stromal Cells ◽

Critical Role ◽

Essential Factor ◽

Transcriptional Responses ◽

Tumour Formation ◽

Different Types ◽

The Impact

AbstractTumours are complex ecosystems composed of different types of cells that communicate and influence each other. While the critical role of stromal cells in affecting tumour growth is well established, the impact of mutant cancer cells on healthy surrounding tissues remains poorly defined. Here, we uncovered a paracrine mechanism by which intestinal cancer cells reactivate foetal and regenerative Yap-associated transcriptional programs in neighbouring wildtype epithelial cells, rendering them adapted to thrive in the tumour context. We identified the glycoprotein Thrombospondin-1 (Thbs1) as the essential factor that mediates non-cell autonomous morphological and transcriptional responses. Importantly, Thbs1 is associated with bad prognosis in several human cancers. This study reveals the Thbs1-YAP axis as the mechanistic link mediating paracrine interactions between epithelial cells, promoting tumour formation and progression.

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