Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (<15 years). In the group of older subjects, we found that the cortico-cortical axonal conduction delays between parcels were globally short (median = 10.2 ms) and only 16% were larger than 20 ms. This was associated to a median velocity of 3.9 m/s. Although a general lengthening of these delays with the distance between the stimulating and recording contacts was observed across the cortex, some regions were less affected by this rule, such as the insula for which almost all efferent and afferent connections were faster than 10 ms. Synaptic time constants were found to be shorter in the sensorimotor, medial occipital and latero-temporal regions, than in other cortical areas. Finally, we found that axonal conduction delays were significantly larger in the group of subjects younger than 15 years, which corroborates that brain maturation increases the speed of brain dynamics. To our knowledge, this study is the first to provide a local estimation of axonal conduction delays and synaptic time constants across the whole human cortex in vivo, based on intracerebral electrophysiological recordings.

• Keywords
• axonal conduction delay, cortico-cortical evoked potential, dynamic causal modelling, neural mass models, synaptic time constant,
• MeSH
• Bayes Theorem MeSH
• Electric Stimulation methods   MeSH
• Epilepsy * MeSH
• Evoked Potentials * physiology   MeSH
• Humans MeSH
• Brain Mapping methods   MeSH
• Brain MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Localization of sound source azimuth within horizontal plane uses interaural time differences (ITDs) between sounds arriving through the left and right ear. In mammals, ITDs are processed primarily in the medial superior olive (MSO) neurons. These are the first binaural neurons in the auditory pathway. The MSO neurons are notable because they possess high time precision in the range of tens of microseconds. Several theories and experimental studies explain how neurons are able to achieve such precision. In most theories, neuronal coincidence detection processes the ITDs and encodes azimuth in ascending neurons of the auditory pathway using modalities that are more tractable than the ITD. These modalities have been described as firing rate codes, place codes (labeled line codes) and similarly. In this theoretical model it is described how the ITD is processed by coincidence detection and converted into spikes by summing the postsynaptic potentials. Particular postsynaptic conductance functions are used in order to obtain an analytical solution in a closed form. Specifically, postsynaptic response functions are derived from the exponential decay of postsynaptic conductances and the MSO neuron is modeled as a simplified version of the Spike Response Model (SRM0) which uses linear summations of the membrane responses to synaptic inputs. For plausible ratios of time constants, an analytical solution used to describe properties of coincidence detection window is obtained. The parameter space is then explored in the vicinity of the analytical solution. The variation of parameters does not change the solution qualitatively.

• Keywords
• Auditory pathway, Coincidence detection, Coincidence window, Medial superior olive, Postsynaptic potential, Sound localization, Spike timing jitter,
• MeSH
• Action Potentials physiology   MeSH
• Humans MeSH
• Sound Localization physiology   MeSH
• Models, Neurological * MeSH
• Nerve Net physiology   MeSH
• Sensory Receptor Cells physiology   MeSH
• Synaptic Transmission physiology   MeSH
• Computer Simulation MeSH
• Auditory Pathways physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission in the CNS. Although these receptors are in direct contact with plasma membrane, lipid-NMDAR interactions are little understood. In the present study, we aimed at characterizing the effect of cholesterol on the ionotropic glutamate receptors. Whole-cell current responses induced by fast application of NMDA in cultured rat cerebellar granule cells (CGCs) were almost abolished (reduced to 3%) and the relative degree of receptor desensitization was increased (by seven-fold) after acute cholesterol depletion by methyl-β-cyclodextrin. Both of these effects were fully reversible by cholesterol repletion. By contrast, the responses mediated by AMPA/kainate receptors were not affected by cholesterol depletion. Similar results were obtained in CGCs after chronic inhibition of cholesterol biosynthesis by simvastatin and acute enzymatic cholesterol degradation to 4-cholesten-3-one by cholesterol oxidase. Fluorescence anisotropy measurements showed that membrane fluidity increased after methyl-β-cyclodextrin pretreatment. However, no change in fluidity was observed after cholesterol enzymatic degradation, suggesting that the effect of cholesterol on NMDARs is not mediated by changes in membrane fluidity. Our data show that diminution of NMDAR responses by cholesterol depletion is the result of a reduction of the open probability, whereas the increase in receptor desensitization is the result of an increase in the rate constant of entry into the desensitized state. Surface NMDAR population, agonist affinity, single-channel conductance and open time were not altered in cholesterol-depleted CGCs. The results of our experiments show that cholesterol is a strong endogenous modulator of NMDARs.

• MeSH
• Anticholesteremic Agents pharmacology   MeSH
• beta-Cyclodextrins pharmacology   MeSH
• Cholesterol Oxidase pharmacology   MeSH
• Cholesterol deficiency   physiology   MeSH
• Electrophysiological Phenomena physiology   MeSH
• Membrane Fluidity drug effects   physiology   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Membrane Lipids physiology   MeSH
• Patch-Clamp Techniques MeSH
• Cerebellum cytology   drug effects   physiology   MeSH
• Neural Conduction physiology   MeSH
• Synaptic Transmission physiology   MeSH
• Rats, Wistar MeSH
• Receptors, N-Methyl-D-Aspartate drug effects   physiology   MeSH
• Simvastatin pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anticholesteremic Agents MeSH
• beta-Cyclodextrins MeSH
• Cholesterol Oxidase MeSH
• Cholesterol MeSH
• Membrane Lipids MeSH
• methyl-beta-cyclodextrin MeSH Browser
• Receptors, N-Methyl-D-Aspartate MeSH
• Simvastatin MeSH

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are highly expressed in the CNS and mediate the slow component of excitatory transmission. The present study was aimed at characterizing the temperature dependence of the kinetic properties of native NMDARs, with special emphasis on the deactivation of synaptic NMDARs. We used patch-clamp recordings to study synaptic NMDARs at layer II/III pyramidal neurons of the rat cortex, recombinant GluN1/GluN2B receptors expressed in human embryonic kidney (HEK293) cells, and NMDARs in cultured hippocampal neurons. We found that time constants characterizing the deactivation of NMDAR-mediated excitatory postsynaptic currents (EPSCs) were similar to those of the deactivation of responses to a brief application of glutamate recorded under conditions of low NMDAR desensitization (whole-cell recording from cultured hippocampal neurons). In contrast, the deactivation of NMDAR-mediated responses exhibiting a high degree of desensitization (outside-out recording) was substantially faster than that of synaptic NMDA receptors. The time constants characterizing the deactivation of synaptic NMDARs and native NMDARs activated by exogenous glutamate application were only weakly temperature sensitive (Q(10)=1.7-2.2), in contrast to those of recombinant GluN1/GluN2B receptors, which are highly temperature sensitive (Q(10)=2.7-3.7). Ifenprodil reduced the amplitude of NMDAR-mediated EPSCs by approximately 50% but had no effect on the time course of deactivation. Analysis of GluN1/GluN2B responses indicated that the double exponential time course of deactivation reflects mainly agonist dissociation and receptor desensitization. We conclude that the temperature dependences of native and recombinant NMDAR are different; in addition, we contribute to a better understanding of the molecular mechanism that controls the time course of NMDAR-mediated EPSCs.

• MeSH
• Excitatory Amino Acid Antagonists pharmacology   MeSH
• Cell Line MeSH
• Excitatory Postsynaptic Potentials drug effects   physiology   MeSH
• Hippocampus drug effects   physiology   MeSH
• Kinetics MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Glutamic Acid metabolism   MeSH
• Humans MeSH
• Cerebral Cortex drug effects   physiology   MeSH
• Synaptic Transmission drug effects   physiology   MeSH
• Piperidines pharmacology   MeSH
• Rats, Wistar MeSH
• Pyramidal Cells drug effects   physiology   MeSH
• Receptors, N-Methyl-D-Aspartate metabolism   MeSH
• Synapses drug effects   physiology   MeSH
• In Vitro Techniques MeSH
• Temperature * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Excitatory Amino Acid Antagonists MeSH
• ifenprodil MeSH Browser
• Glutamic Acid MeSH
• Piperidines MeSH
• Receptors, N-Methyl-D-Aspartate MeSH

N-methyl-D-aspartate (NMDA) receptors are highly expressed in the CNS, mediate the slow component of excitatory transmission and play key roles in synaptic plasticity and excitotoxicity. These ligand-gated ion channels are heteromultimers composed of NR1 and NR2 subunits activated by glycine and glutamate. In this study, patch-clamp recordings were used to study the temperature sensitivity of recombinant NR1/NR2B receptors expressed in human embryonic kidney (HEK) 293 cells. Rate constants were assessed by fitting a six-state kinetic scheme to time courses of transient macroscopic currents induced by glutamate at 21.9-46.5 degrees C. Arrhenius transformation of the rate constants characterizing NMDA receptor channel activity indicates that the most sensitive were the rate constants of desensitization (temperature coefficient Q(10)=10.3), resensitization (Q(10)=4.6) and unbinding (Q(10)=3.6). Other rate constants and the amplitude of single-channel currents were less temperature sensitive. Deactivation of responses mediated by NR1/NR2B receptors after a brief application of glutamate was best fit by a double exponential function (tau(fast): Q(10)=3.7; tau(slow): Q(10)=2.7). From these data, we conclude that desensitization/resensitization of the NMDA receptor and glutamate unbinding are especially temperature sensitive and imply that at physiological temperatures the channel kinetics play an important role in determining amplitude and time course of NMDA receptor-mediated postsynaptic currents and these receptors mediated synaptic plasticity.

• MeSH
• Algorithms MeSH
• Cell Line MeSH
• Electrophysiology MeSH
• Ion Channel Gating physiology   MeSH
• Kinetics MeSH
• Glutamic Acid metabolism   MeSH
• Kidney cytology   metabolism   MeSH
• Humans MeSH
• Patch-Clamp Techniques MeSH
• Receptors, N-Methyl-D-Aspartate drug effects   genetics   physiology   MeSH
• Recombinant Proteins MeSH
• Models, Statistical MeSH
• In Vitro Techniques MeSH
• Temperature MeSH
• Transfection MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glutamic Acid MeSH
• NR1 NMDA receptor MeSH Browser
• NR2B NMDA receptor MeSH Browser
• Receptors, N-Methyl-D-Aspartate MeSH
• Recombinant Proteins MeSH

Five parameters of one of the most common neuronal models, the diffusion leaky integrate-and-fire model, also known as the Ornstein-Uhlenbeck neuronal model, were estimated on the basis of intracellular recording. These parameters can be classified into two categories. Three of them (the membrane time constant, the resting potential and the firing threshold) characterize the neuron itself. The remaining two characterize the neuronal input. The intracellular data were collected during spontaneous firing, which in this case is characterized by a Poisson process of interspike intervals. Two methods for the estimation were applied, the regression method and the maximum-likelihood method. Both methods permit to estimate the input parameters and the membrane time constant in a short time window (a single interspike interval). We found that, at least in our example, the regression method gave more consistent results than the maximum-likelihood method. The estimates of the input parameters show the asymptotical normality, which can be further used for statistical testing, under the condition that the data are collected in different experimental situations. The model neuron, as deduced from the determined parameters, works in a subthreshold regimen. This result was confirmed by both applied methods. The subthreshold regimen for this model is characterized by the Poissonian firing. This is in a complete agreement with the observed interspike interval data.

• MeSH
• Action Potentials physiology   MeSH
• Cell Membrane physiology   MeSH
• Humans MeSH
• Brain physiology   MeSH
• Neural Pathways physiology   MeSH
• Synaptic Transmission physiology   MeSH
• Neural Networks, Computer * MeSH
• Neurons physiology   MeSH
• Signal Processing, Computer-Assisted MeSH
• Poisson Distribution MeSH
• Stochastic Processes MeSH
• Synapses physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

A novel derivative of 6-methyluracil, C-547, increased the amplitude and prolonged the duration of miniature endplate currents (MEPCs) which is typical for acetylcholinesterase inhibition. In the soleus and extensor digitorum longus significant potentiation was detected at nanomolar concentrations. In contrast, in the diaphragm muscle, the increase in the amplitudes of the MEPCs and the decay time constant appeared only when the concentration of C-547 was elevated to 1 x 10(-7) M. Possible consequences for the exploitation of this drug, which can selectively inhibit AChE in particular synapses, are discussed.

• MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Electrophysiology MeSH
• Muscle, Skeletal drug effects   innervation   physiology   MeSH
• Rats MeSH
• Quaternary Ammonium Compounds chemistry   pharmacology   MeSH
• Molecular Structure MeSH
• Motor Endplate drug effects   physiology   MeSH
• Synaptic Transmission drug effects   physiology   MeSH
• Rats, Wistar MeSH
• In Vitro Techniques MeSH
• Uracil analogs & derivatives   chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• C-547 compound MeSH Browser
• Cholinesterase Inhibitors MeSH
• Quaternary Ammonium Compounds MeSH
• Uracil MeSH

We study optimal estimation of a signal in parametric neuronal models on the basis of interspike interval data. Fisher information is the inverse asymptotic variance of the best estimator. Its dependence on the parameter value indicates accuracy of estimation. Our models assume that the input signal is estimated from neuronal output interspike interval data where the frequency transfer function is sigmoidal. If the coefficient of variation of the interspike interval is constant with respect to the signal, the Fisher information is unimodal, and its maximum for the most estimable signal can be found. We obtain a general result and compare the signal producing maximal Fisher information with the inflection point of the sigmoidal transfer function in several basic neuronal models.

• MeSH
• Action Potentials physiology   MeSH
• Time Factors MeSH
• Entropy MeSH
• Models, Neurological * MeSH
• Synaptic Transmission physiology   MeSH
• Neural Inhibition MeSH
• Neurons physiology   MeSH
• Computer Simulation * MeSH
• Poisson Distribution MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH

NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission and synaptic plasticity as well as excitotoxicity. They have several binding sites for allosteric modulators, including neurosteroids, endogenous compounds synthesized by the nervous tissue and expected to act locally. Whole-cell patch-clamp recording from human embryonic kidney 293 cells expressing NR1-1a/NR2B receptors revealed that neurosteroid pregnenolone sulfate (PS) (300 microm), when applied to resting NMDA receptors, potentiates the amplitude of subsequent responses to 1 mm glutamate fivefold and slows their deactivation twofold. The same concentration of PS, when applied during NMDA receptor activation by 1 mm glutamate, has only a small effect. The association and dissociation rate constants of PS binding and unbinding from resting NMDA receptors are estimated to be 3.3 +/- 2.0 mm(-1)sec(-1) and 0.12 +/- 0.02 sec(-1), respectively, corresponding to an apparent affinity K(d) of 37 microm. The results of experiments indicate that the molecular mechanism of PS potentiation of NMDA receptor responses is attributable to an increase in the peak channel open probability (P(o)). Responses to glutamate recorded in the continuous presence of PS exhibit marked time-dependent decline. Our results indicate that the decline is induced by a change of the NMDA receptor affinity for PS after receptor activation. These results suggest that the PS is a modulator of NMDA receptor P(o), the effectiveness of which is lowered by glutamate binding. This modulation may have important consequences for the neuronal excitability.

• MeSH
• Models, Biological MeSH
• Ion Channel Gating drug effects   MeSH
• Hippocampus cytology   MeSH
• Kinetics MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Glutamic Acid pharmacology   MeSH
• Humans MeSH
• Patch-Clamp Techniques MeSH
• Neurons drug effects   metabolism   MeSH
• Animals, Newborn MeSH
• Probability MeSH
• Pregnenolone pharmacology   MeSH
• Receptors, N-Methyl-D-Aspartate agonists   drug effects   metabolism   MeSH
• Recombinant Proteins agonists   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glutamic Acid MeSH
• NR1 NMDA receptor MeSH Browser
• NR2B NMDA receptor MeSH Browser
• Pregnenolone MeSH
• pregnenolone sulfate MeSH Browser
• Receptors, N-Methyl-D-Aspartate MeSH
• Recombinant Proteins MeSH

Replacing static synapses with the adaptive ones can affect the behaviour of neuronal network. Several network setups containing synapses modelled by alpha-functions, called here static synapses, are compared with corresponding setups containing more complex, dynamic synapses. The dynamic synapses have four state variables and the time constants are of different orders of magnitude. Response of the network to modelled stimulations was studied together with effects of neuronal interconnectivity, the axonal delays and the proportion of excitatory and inhibitory neurons on the network output. Dependency of synaptic strength on synaptic activity was also studied. We found that dynamic synapses enable network to exhibit broader spectrum of responses to given input and they make the network more sensitive to changes of network parameters. As a step towards memory modelling, retention of input sequences in the network with static and dynamic synapses was studied. The network with dynamic synapses was found to be more flexible in reducing the interference between adjacent inputs in comparison to the network containing static synapses.

• MeSH
• Humans MeSH
• Models, Neurological * MeSH
• Nerve Net * MeSH
• Synapses physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH