Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to a successive stimulus

Rienecker, Kira D. A.; Poston, Robert G.; Segales, Joshua S.; Finholm, Isabelle W.; Sono, Morgan H.; Munteanu, Sorina J.; Ghaninejad-Esfahani, Mina; Rejepova, Ayna; Tejeda-Garibay, Susana; Wickman, Kevin; Velasco, Ezequiel Marrón Fernández de; Thayer, Stanley A.; Saha, Ramendra N.

doi:10.1016/j.jbc.2022.102278

Cited by 16 publications

(6 citation statements)

References 83 publications

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“…In the CNS, c-Fos, Egr1, and Arc are used as a markers of neuronal activity in the context of memory formation and development of multiple psychiatric disorders such as SZ and ASD ( Minatohara et al, 2016 ; Gallo et al, 2018 ). It was previously shown that multiple IEGs, including Egr1, Egr4, c-Fos, c-Jun, Naps4, Nur77, and Arc were upregulated in in vivo animal (from rodents to primates) and in in vitro models of epilepsy, as was confirmed in our study ( Kiessling and Gass, 1993 ; Barros et al, 2015 ; Kalinina et al, 2022 ; Rienecker et al, 2022 ). However, in contrast to earlier studies that used in situ hybridization, repetitive stimulations with PTZ, or using the earliest time-point at 30 min, we used more sensitive quantitative real-time PCR, which allowed us to detect upregulation of ten IEGs within a 9 ± 1 min period post-PTZ injections to ensure that all tested animals are alive.…”

Section: Discussionsupporting

confidence: 90%

Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes

Veremeyko

Jiang

et al. 2023

Front. Cell. Neurosci.

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Complement system plays an important role in the immune defense against pathogens; however, recent studies demonstrated an important role of complement subunits C1q, C4, and C3 in normal functions of the central nervous system (CNS) such as non-functional synapse elimination (synapse pruning), and during various neurologic pathologies. Humans have two forms of C4 protein encoded by C4A and C4B genes that share 99.5% homology, while mice have only one C4B gene that is functionally active in the complement cascade. Overexpression of the human C4A gene was shown to contribute to the development of schizophrenia by mediating extensive synapse pruning through the activation C1q-C4-C3 pathway, while C4B deficiency or low levels of C4B expression were shown to relate to the development of schizophrenia and autism spectrum disorders possibly via other mechanisms not related to synapse elimination. To investigate the potential role of C4B in neuronal functions not related to synapse pruning, we compared wildtype (WT) mice with C3- and C4B- deficient animals for their susceptibility to pentylenetetrazole (PTZ)- induced epileptic seizures. We found that C4B (but not C3)–deficient mice were highly susceptible to convulsant and subconvulsant doses of PTZ when compared to WT controls. Further gene expression analysis revealed that in contrast to WT or C3-deficient animals, C4B-deficient mice failed to upregulate expressions of multiple immediate early genes (IEGs) Egrs1-4, c-Fos, c-Jus, FosB, Npas4, and Nur77 during epileptic seizures. Moreover, C4B-deficient mice had low levels of baseline expression of Egr1 on mRNA and protein levels, which was correlated with the cognitive problems of these animals. C4-deficient animals also failed to upregulate several genes downstream of IEGs such as BDNF and pro-inflammatory cytokines IL-1β, IL-6, and TNF. Taken together, our study demonstrates a new role of C4B in the regulation of expression of IEGs and their downstream targets during CNS insults such as epileptic seizures.

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Section: Discussionsupporting

confidence: 90%

Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes

Veremeyko

Jiang

et al. 2023

Front. Cell. Neurosci.

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“…Therefore, ACBI1 degrades major BAF complex subunits to various degrees but leaves intact some protein orphans from the complex, such as SMARCC2 and SS18L1. Next, sustained synaptic activity was stimulated with Bicuculline and 4-Aminopyridine (Bic+4AP) for 15 minutes and transcriptional response was assessed by quantifying Arc pre-mRNA 54,55 . Fifteen minutes of activity was chosen to isolate transcription of rIEGs from other activity-induced transcription, which are detectable later in the hour 50,51 .…”

Section: Resultsmentioning

confidence: 99%

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Cornejo,

Venegas,

Sono

et al. 2023

Preprint

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Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 overcome nucleosomal barriers. Using RNAi, three degraders, and several small molecule inhibitors, we show that the mammalian SWI/SNF complex of neurons (neuronal BAF, or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal Pol2 pausing, signal-dependent Pol2 recruitment (loading), and importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent Pol2. Mechanistically, Pol2 elongation is mediated by activity-induced nBAF assembly (especially, ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of Pol2 transcription and reveal mechanisms underlying activity-induced Pol2 elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions.

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“…15 When an ischemic process occurs, a condition of oxygen and glucose deprivation occurs, so that within minutes, neuronal cells and non-neuronal cells will be depolarized and calcium channel activation occurs. 16 The depolarization will also release excitatory neurotransmitters from the presynaptic terminal to the synapse gap. For one, the released glutamate will bind to the ionotropic receptors N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoazole propionic acid (AMPA).…”

Section: Discussionmentioning

confidence: 99%

Effect of Thiamine on Serum Glutamate in Ischemic Stroke Animal Model

Ardhi¹,

Hamdan²,

Romdhoni³

2023

Pharmacogn J.

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This research is a True Experimental with a research design using a design in the form of a randomized posttest only control group design. Experimental animalThe experimental unit used in this study was male rats (Rattus novergicus) Wistar strain, white in color, 4 months old weighing 140-200 grams. Then the stroke model was carried out by occluding the left carotid artery. Then the population was randomized with a total of 32 samples. Then divided into 4 groups: control, thiamine doses of 100 mg/kg/ day, 200 mg/kg/day and 400 mg/kg/day. Analysis of glutamateExamination of serum glutamate levels was carried out on day 7 with blood serum material, using an ELISA Reader, Rat GLUD1/Glutamate ELISA Kit reagent, the method used was sandwich ELISA, unit mg/mL. Glutamate levels were measured with Rat Glutamate ELISA Kit (Wuhan Feiyue Biotechnology Co., Ltd. Catalog No: FY-ER4835).

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Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to a successive stimulus

Cited by 16 publications

References 83 publications

Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes

Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Effect of Thiamine on Serum Glutamate in Ischemic Stroke Animal Model

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