1,720,957 research outputs found
A REST/NRSF-dependent transcriptional remodeling governs GABAergic synaptic upscaling induced by chronic hyperactivity
No full textREST/NRFS (RE1-silencing transcription factor) has been initially identified as a negative transcription factor. Its target genes encode postsynaptic receptors, ion channels and transporters, neuropeptides and synaptic proteins. Evidences show that in mature neurons, REST can be upregulated by neuronal hyperactivity and works as a master epigenetic modulator, acting mostly as transcriptional repressor and, occasionally, as a transcriptional activator (Perera et al., 2015; Kallunki et al., 1998). We have previously demonstrated that REST is critical for the downscaling of intrinsic excitability in excitatory neurons subjected to prolonged elevation of electrical activity (Pozzi et al., 2013) and that it participates to the synaptic homeostasis of glutamatergic synapses by reducing their strength at the presynaptic level (Pecoraro-Bisogni et al., 2017). The aim of our work is to verify if REST plays a role in the synaptic homeostasis of GABAergic transmission evoked by hyperexcitability. Here we show that neuronal hyperactivity, obtained by treating for two days primary hippocampal neurons with 4-aminopyridine (4AP), induces a REST-dependent potentiation of the strength and number of somatic GABAergic synapses onto excitatory neurons, while the effect was lacking when the postsynaptic target cell was another inhibitory neuron. Our data suggest that the postsynaptic target specificity depends on a REST-dependent induction of a downstream transcription factor, NPAS4, known for its role in the development of inhibitory synapses, thanks to its capability of activating BDNF release from excitatory neurons upon hyperactivity (Lin et al. 2008). BDNF is synthetized only by excitatory neurons (Hofer et al., 1990). Thus, the retrograde action of BDNF, released from the soma of excitatory neurons onto the somatic GABAergic presynaptic contacts, could explain the observed postsynaptic target specificity of REST-action
Spike-Related Electrophysiological Identification of Cultured Hippocampal Excitatory and Inhibitory Neurons
No full textCultured hippocampal neurons represent the most widely used experimental substrate for in vitro electrophysiological studies. Nevertheless, in most cases, the nature of neuron under study is not identified as excitatory or inhibitory, or even worse, recorded neurons are considered as excitatory because of the paucity of GABAergic interneurons. Thus, the definition of reliable criteria able to guarantee an unequivocal identification of excitatory and inhibitory cultured hippocampal neurons is an unmet need. To reach this goal, we compared the electrophysiological properties and the localization and size of the axon initial segment (AIS) of cultured hippocampal neurons, taking advantage from GAD67-GFP knock-in mice, which expressing green fluorescent protein (GFP) in gamma-aminobutyric acid (GABA)–containing cells, allowed to unambiguously determine the precise nature of the neuron under study. Our results demonstrate that the passive electrophysiological properties, the localization and size of the AIS, and the shape and frequency of the action potential (AP) are not reliable to unequivocally identify neurons as excitatory or inhibitory. The only parameter, related to the shape of the single AP, showing minimal overlap between the sample-point distributions of the two neuronal subpopulations, was the AP half-width. However, the estimation of the AP failure ratio evoked by a short train of high-current steps applied at increasing frequency (40–140 Hz) resulted to be indisputably the safer and faster way to identify the excitatory or inhibitory nature of an unknown neuron. Our findings provide a precise framework for further electrophysiological investigations of in vitro hippocampal neurons
Harnessing metabolic control for synaptic stability: REST/NRSF links glycolytic inhibition to excitatory neurotransmission
No full textAbstract: Under resting conditions most neuronal ATP is produced through mitochondrial oxidative phosphorylation, whereas glycolysis becomes more important during intense neuronal firing. Recent studies suggest that inhibiting glycolysis plays a key role in regulating seizure-related hyperactivity, with the epigenetic modulator REST/NRSF being activated when glycolysis inhibition lowers the NADH/NAD+ ratio. Our previous research has shown that REST/NRSF initiates homeostatic processes to counteract neuronal hyperactivity by regulating both firing and synaptic activities. However, the exact mechanism through which the metabolic activation of REST/NRSF controls neuronal excitability is still unknown. Here, we studied the role of REST/NRSF in the effects of glycolysis inhibition on hippocampal neuron activity. Treatment with 2-deoxy-d-glucose (2DG) decreased the NADH/NAD+ ratio, increased REST/NRSF expression, and promoted its nuclear translocation. Although GABAergic inhibitory inputs and the firing properties of both excitatory and inhibitory neurons were unaffected by 2DG, the amplitude of evoked EPSCs (eEPSCs) and miniature EPSCs (mEPSCs) was reduced in a REST/NRSF-dependent manner. This effect was associated with a REST/NRSF-dependent reduction in the size of GluA2-positive puncta and a decrease in GluA2 expression in the absence of changes in the density of excitatory synapses. These effects provide a mechanistic basis for the significant reduction in network firing and bursting activity observed when the hippocampal network was treated with 2DG. These findings highlight a role of the REST/NRSF-dependent pathway in the 2DG-mediated downregulation of excitatory inputs, a mechanism that contributes to neuronal network stability, strengthening the homeostatic defences against hyperactivity. (Figure presented.). Key points: Reducing glucose metabolism with 2-deoxy-d-glucose (2DG) lowers the cell's energy balance and increases the levels of a gene regulator called REST/NRSF. REST/NRSF then moves into the nucleus, where it controls the activity of genes linked to nerve cell communication. 2DG weakens the strength of signals between excitatory nerve cells, without affecting inhibitory signals or the basic ability of neurons to fire. This effect depends in part on REST/NRSF, which reduces the amount and size of GluA2-containing AMPA receptors at excitatory synapses, without altering the overall number of excitatory contacts. These findings suggest that blocking glucose metabolism activates a protective response that stabilizes brain networks, which could help control seizures in epilepsy
Low glycemic index diet restrains epileptogenesis in a gender-specific fashion
No full text: Dietary restriction, such as low glycemic index diet (LGID), have been successfully used to treat drug-resistant epilepsy. However, if such diet could also counteract antiepileptogenesis is still unclear. Here, we investigated whether the administration of LGID during the latent pre-epileptic period, prevents or delays the appearance of the overt epileptic phenotype. To this aim, we used the Synapsin II knockout (SynIIKO) mouse, a model of temporal lobe epilepsy in which seizures manifest 2-3 months after birth, offering a temporal window in which LGID may affect epileptogenesis. Pregnant SynIIKO mice were fed with either LGID or standard diet during gestation and lactation. Both diets were maintained in weaned mice up to 5 months of age. LGID delayed the seizure onset and induced a reduction of seizures severity only in female SynIIKO mice. In parallel with the epileptic phenotype, high-density multielectrode array recordings revealed a reduction of frequency, amplitude, duration, velocity of propagation and spread of interictal events by LGID in the hippocampus of SynIIKO females, but not mutant males, confirming the gender-specific effect. ELISA-based analysis revealed that LGID increased cortico-hippocampal allopregnanolone (ALLO) levels only in females, while it was unable to affect ALLO plasma concentrations in either sex. The results indicate that the gender-specific interference of LGID with the epileptogenic process can be ascribed to a gender-specific increase in cortical ALLO, a neurosteroid known to strengthen GABAergic transmission. The study highlights the possibility of developing a personalized gender-based therapy for temporal lobe epilepsy
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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