Linear to Supralinear Summation of AMPA-Mediated EPSPs in Neocortical Pyramidal Neurons

2000 ◽  
Vol 83 (6) ◽  
pp. 3310-3322 ◽  
Author(s):  
Jilda S. Nettleton ◽  
William J. Spain
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Coincidence Detection ◽  
Layer V ◽  
Layer I ◽  
The Individual ◽  
Dc Current ◽  
Neocortical Pyramidal Neurons

It has been hypothesized that voltage-sensitive conductances present on the dendrites of neurons can influence summation of excitatory postsynaptic potentials (EPSPs) and hence affect how neurons compile information. Greater than linear summation of EPSPs has been postulated to facilitate coincidence detection by cortical neurons. This study examined whether the summation of subthreshold AMPA-mediated EPSPs generated on layer V neocortical pyramidal neurons in vitro was linear and if any nonlinearities could be attributed to dendritic conductances. Evoked EPSPs (1–12 mV) were recorded somatically by means of intracellular sharp electrodes in the presence of 100 μM amino-5-phosphonopentanoic acid (AP-5) and 3 μM bicuculline. Two independent EPSPs were evoked by a stimulating electrode in layer I and another in layers III–V. The areas of stimulation were isolated from each other by a horizontal cut below layer I. By subtracting the algebraic sum of the individual EPSPs from the evoked response when both EPSPs were evoked simultaneously, we determined that they summed linearly to supralinearly. Supralinear summation was more likely when the soma was hyperpolarized by DC current injection. Summation was predominantly linear when postsynaptic conductances (i.e., Na+ and Ca2+) were blocked with intracellular QX-314. The supralinear summation of EPSPs (without QX-314) decreased as the time between inputs was increased from 0 to 30 ms. To determine the role of dendrites in nonlinear summation, we substituted a current pulse (simulated EPSP) delivered at the soma for either or both of the evoked EPSPs. Simulated EPSPs combined with either an evoked EPSP or another simulated EPSP showed significantly less supralinear summation than two evoked EPSPs, indicating that the dendritic conductances were largely responsible for the observed supralinear summation.

Impact of Spontaneous Synaptic Activity on the Resting Properties of Cat Neocortical Pyramidal Neurons In Vivo

1998 ◽  
Vol 79 (3) ◽  
pp. 1450-1460 ◽  
Author(s):  
Denis Paré ◽  
Eric Shink ◽  
Hélène Gaudreau ◽  
Alain Destexhe ◽  
Eric J. Lang
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Synaptic Activity ◽  
Intact Brain ◽  
Lower Temperature ◽  
The Impact ◽  
Neocortical Pyramidal Neurons

Paré, Denis, Eric Shink, Hélène Gaudreau, Alain Destexhe, and Eric J. Lang. Impact of spontaneous synaptic activity on the resting properties of cat neocortical pyramidal neurons in vivo. J. Neurophysiol. 79: 1450–1460, 1998. The frequency of spontaneous synaptic events in vitro is probably lower than in vivo because of the reduced synaptic connectivity present in cortical slices and the lower temperature used during in vitro experiments. Because this reduction in background synaptic activity could modify the integrative properties of cortical neurons, we compared the impact of spontaneous synaptic events on the resting properties of intracellularly recorded pyramidal neurons in vivo and in vitro by blocking synaptic transmission with tetrodotoxin (TTX). The amount of synaptic activity was much lower in brain slices (at 34°C), as the standard deviation of the intracellular signal was 10–17 times lower in vitro than in vivo. Input resistances ( R ins) measured in vivo during relatively quiescent epochs (“control R ins”) could be reduced by up to 70% during periods of intense spontaneous activity. Further, the control R ins were increased by ∼30–70% after TTX application in vivo, approaching in vitro values. In contrast, TTX produced negligible R in changes in vitro (∼4%). These results indicate that, compared with the in vitro situation, the background synaptic activity present in intact networks dramatically reduces the electrical compactness of cortical neurons and modifies their integrative properties. The impact of the spontaneous synaptic bombardment should be taken into account when extrapolating in vitro findings to the intact brain.

Dopamine Increases the Gain of the Input-Output Response of Rat Prefrontal Pyramidal Neurons

2008 ◽  
Vol 99 (6) ◽  
pp. 2985-2997 ◽  
Author(s):  
Kay Thurley ◽  
Walter Senn ◽  
Hans-Rudolf Lüscher
Keyword(s):  
Working Memory ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
D1 Receptors ◽  
Input Output ◽  
Prefrontal Cortical ◽  
Noisy Input ◽  
Relationship Of

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.

Effect of Ginkgo biloba extract on rat hepatic microsomal CYP1A activity: role of ginkgolides, bilobalide, and flavonols

2004 ◽  
Vol 82 (1) ◽  
pp. 57-64 ◽  
Author(s):  
I fan Kuo ◽  
Jie Chen ◽  
Thomas K.H Chang
Keyword(s):  
Ginkgo Biloba ◽  
Ginkgo Biloba Extract ◽  
Inhibitory Potency ◽  
Hepatic Microsomes ◽  
Cyp1a Activity ◽  
Ginkgo Biloba Extracts ◽  
The Individual ◽  
Vitro Effect

The present study investigated the in vitro effect of Ginkgo biloba extracts and some of the individual constituents (ginkgolides, bilobalide, and flavonols such as kaempferol, quercetin, isorhamnetin, and their glycosides) on CYP1A-mediated 7-ethoxyresorufin O-dealkylation in hepatic microsomes isolated from rats induced with β-naphthoflavone. G. biloba extract competitively inhibited CYP1A activity, with an apparent Ki value of 1.6 ± 0.4 µg/mL (mean ± SE). At the concentrations present in the G. biloba extracts, ginkgolides A, B, C, and J and bilobalide did not affect CYP1A activity, whereas kaempferol (IC50 = 0.006 ± 0.001 µg/mL, mean ± SE), isorhamnetin (0.007 ± 0.001 µg/mL), and quercetin (0.050 ± 0.003 µg/mL) decreased this activity. The monoglycosides (1 and 10 µg/mL) and diglycosides (10 µg/mL) of kaempferol and quercetin but not those of isorhamnetin also inhibited CYP1A activity. The order of inhibitory potency was kaempferol ~ isorhamnetin > quercetin, and for each of these flavonols the order of potency was aglycone >> monoglycoside > diglycoside. In summary, G. biloba extract competitively inhibited rat hepatic microsomal CYP1A activity, but the effect was not due to ginkgolides A, B, C, or J, bilobalide, kaempferol, quercetin, isorhamnetin, or the respective flavonol monoglycosides or diglycosides.Key words: bilobalide, CYP1A, cytochrome P450, Ginkgo biloba, ginkgolide, flavonol.

Simulations of Intrinsically Bursting Neocortical Pyramidal Neurons

1994 ◽  
Vol 6 (6) ◽  
pp. 1086-1110 ◽  
Author(s):  
Paul A. Rhodes ◽  
Charles M. Gray
Keyword(s):  
Visual Cortex ◽  
Ion Channels ◽  
Pyramidal Neurons ◽  
Compartment Model ◽  
Morphological Data ◽  
High Threshold ◽  
Simulation Results ◽  
Dendritic Branches ◽  
Neocortical Pyramidal Neurons

Neocortical layer 5 intrinsically bursting (IB) pyramidal neurons were simulated using compartment model methods. Morphological data as well as target neurophysiological responses were taken from a series of published studies on the same set of rat visual cortex pyramidal neurons (Mason, A. and Larkman, A. J., 1990. J. Neurosci. 9,1440-1447; Larkman, A. J. 1991. J. Comp. Neurol. 306, 307-319). A dendritic distribution of ion channels was found that reproduced the range of in vitro responses of layer 5 IB pyramidal neurons, including the transition from repetitive bursting to the burst/tonic spiking mode seen in these neurons as input magnitude increases. In light of available data, the simulation results suggest that in these neurons bursts are driven by an inward flow of current during a high threshold Ca2+ spike extending throughout both the basal and apical dendritic branches.

Differential Roles of NMDA Receptor Subtypes NR2A and NR2B in Dendritic Branch Development and Requirement of RasGRF1

2010 ◽  
Vol 103 (4) ◽  
pp. 1758-1770 ◽  
Author(s):  
Fernando J. Sepulveda ◽  
Fernando J. Bustos ◽  
Eveling Inostroza ◽  
Felipe A. Zúñiga ◽  
Rachael L. Neve ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Receptor Subtypes ◽  
Dendritic Branch ◽  
Spinal Cord Neurons ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings ◽  
Branch Formation ◽  
The Individual

N-methyl-d-aspartate receptors (NMDARs) are known to regulate axonal refinement and dendritic branching. However, because NMDARs are abundantly present as tri-heteromers (e.g., NR1/NR2A/NR2B) during development, the precise role of the individual subunits NR2A and NR2B in these processes has not been elucidated. Ventral spinal cord neurons (VSCNs) provide a unique opportunity to address this problem, because the expression of both NR2A and NR2B (but not NR1) is downregulated in culture. Exogenous NR2A or NR2B were introduced into these naturally NR2-null neurons at 4 DIV, and electrophysiological recordings at 11 DIV confirmed that synaptic NR1NR2A receptors and NR1NR2B receptors were formed, respectively. Analysis of the dendritic architecture showed that introduction of NR2B, but not NR2A, dramatically increased the number of secondary and tertiary dendritic branches of VSCNs. Whole cell patch-clamp recordings further indicated that the newly formed branches in NR2B-expressing neurons were able to establish functional synapses because the frequency of miniature AMPA-receptor synaptic currents was increased. Using previously described mutants, we also found that disruption of the interaction between NR2B and RasGRF1 dramatically impaired dendritic branch formation in VSCNs. The differential role of the NR2A and NR2B subunits and the requirement for RasGRF1 in regulating branch formation was corroborated in hippocampal cultures. We conclude that the association between NR1NR2B-receptors and RasGRF1 is needed for dendritic branch formation in VSCNs and hippocampal neurons in vitro. The dominated NR2A expression and the limited interactions of this subunit with the signaling protein RasGRF1 may contribute to the restricted dendritic arbor development in the adult CNS.

scholarly journals Selective corticostriatal plasticity during acquisition of an auditory discrimination task

2014 ◽  
Author(s):  
Qiaojie Xiong ◽  
Petr Znamenskiy ◽  
Anthony Zador
Keyword(s):  
Cortical Neurons ◽  
Brain Slices ◽  
Frequency Discrimination ◽  
Auditory Discrimination ◽  
Low Frequencies ◽  
Reward Contingencies ◽  
Corticostriatal Plasticity

Perceptual decisions are based on the activity of sensory cortical neurons, but how organisms learn to transform this activity into appropriate actions remains unknown. Projections from the auditory cortex to the auditory striatum carry information that drives decisions in an auditory frequency discrimination task1. To assess the role of these projections in learning, we developed a Channelrhodopsin-2-based assay to selectively probe for synaptic plasticity associated with corticostriatal neurons representing different frequencies. Here we report that learning this auditory discrimination preferentially potentiates corticostriatal synapses from neurons representing either high or low frequencies, depending on reward contingencies. We observed frequency-dependent corticostriatal potentiation in vivo over the course of training, and in vitro in striatal brain slices. Our findings suggest a model in which selective potentiation of inputs representing different components of a sensory stimulus enables the learned transformation of sensory input into actions.

scholarly journals In Vitro Mutagenic and Genotoxic Assessment of a Mixture of the Cyanotoxins Microcystin-LR and Cylindrospermopsin

Toxins ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 318 ◽  
Author(s):  
Leticia Díez-Quijada ◽  
Ana I. Prieto ◽  
María Puerto ◽  
Ángeles Jos ◽  
Ana M. Cameán
Keyword(s):  
Risk Evaluation ◽  
Evaluation Framework ◽  
Kinase Assay ◽  
In Vitro Tests ◽  
Food Contaminants ◽  
The Individual ◽  
Mutation Assay ◽  
Mouse Lymphoma

The co-occurrence of various cyanobacterial toxins can potentially induce toxic effects different than those observed for single cyanotoxins, as interaction phenomena cannot be discarded. Moreover, mixtures are a more probable exposure scenario. However, toxicological information on the topic is still scarce. Taking into account the important role of mutagenicity and genotoxicity in the risk evaluation framework, the objective of this study was to assess the mutagenic and genotoxic potential of mixtures of two of the most relevant cyanotoxins, Microcystin-LR (MC-LR) and Cylindrospermopsin (CYN), using the battery of in vitro tests recommended by the European Food Safety Authority (EFSA) for food contaminants. Mixtures of 1:10 CYN/MC-LR (CYN concentration in the range 0.04–2.5 µg/mL) were used to perform the bacterial reverse-mutation assay (Ames test) in Salmonella typhimurium, the mammalian cell micronucleus (MN) test and the mouse lymphoma thymidine-kinase assay (MLA) on L5178YTk± cells, while Caco-2 cells were used for the standard and enzyme-modified comet assays. The exposure periods ranged between 4 and 72 h depending on the assay. The genotoxicity of the mixture was observed only in the MN test with S9 metabolic fraction, similar to the results previously reported for CYN individually. These results indicate that cyanobacterial mixtures require a specific (geno)toxicity evaluation as their effects cannot be extrapolated from those of the individual cyanotoxins.

Modulation of factor VII levels by intron 7 polymorphisms: population and in vitro studies

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3423-3428 ◽  
Author(s):  
Mirko Pinotti ◽  
Raffaella Toso ◽  
Domenico Girelli ◽  
Debora Bindini ◽  
Paolo Ferraresi ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Fold Increase ◽  
Factor Vii ◽  
The Novel ◽  
Expression Studies ◽  
Sequence Variations ◽  
Fvii Deficiency ◽  
The Individual

Abstract Previous studies have established that factor VII gene (F7) polymorphisms (5′F7 and R353Q) contribute about one-third of factor VII (FVII) level variation in plasma. However, F7 genotyping in patients with cardiovascular disease has produced conflicting results. Population and expression studies were used to investigate the role of intron 7 (IVS7 ) polymorphisms, including repeat and sequence variations, in controlling activated FVII (FVIIa) and antigen (FVIIag) levels. Genotype–phenotype studies performed in 438 Italian subjects suggested a positive relation between the IVS7 repeat number and FVII levels. The lowest values were associated with theIVS7 + 7G allele. The screening of 52 patients with mild FVII deficiency showed an 8-fold increase in frequency (8%) of this allele, and among heterozygotes for identical mutations, lower FVII levels were observed in the IVS7 + 7G carriers. This frequent genetic component participates in the phenotypic heterogeneity of FVII deficiency. The evaluation of the individual contribution of polymorphisms was assisted by the expression of each IVS7variant, as a minigene, in eukaryotic cells. The novel quantitative analysis revealed that higher numbers of repeats were associated with higher mRNA expression levels and that the IVS7 + 7Gallele, previously defined as a functionally silent polymorphism, was responsible for the lowest relative mRNA expression. Taken together, these findings indicate that the IVS7 polymorphisms contribute to the plasmatic variance of FVII levels via differential efficiency of mRNA splicing. These studies provide further elements to understand the control of FVII levels, which could be of importance to ensure the hemostatic balance under pathologic conditions.

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