Dynamic model of neuronal response in the rat hippocampus

A linear lumped model was proposed for the hippocampal CA 1 region of anesthetized rats using differential equations of time-independent coefficients, the afferent and efferent fibers of the alveus as inputs and the averaged evoked potentials (AEPs) and poststimulus time histograms as outputs. The alvear tract, a major efferent path, was proposed to activate interneurons monosynaptically while the anterior alveus activated orthodromically pyramidal cells which then excited the interneurons. The interneurons then inhibited pyramidal cells. The observable field outputs were the excitatory postsynaptic potentials (EPSPs) of interneurons and the inhibitory postsynaptic potentials (IPSPs) of pyramidal cells. Positive neurophysiological feedbacks were proposed among interneurons and among pyramidal cells in order to account for the prolonged time courses of the interneuronal EPSPs and the pyramidal cell IPSPs. The parameters of the model were optimized by a nonlinear regression program which minimized the sum of squared deviations between the model-generated and actual AEPs. The parameters included the temporal dispersion of the input tract (about 3 ms) and the membrane time constant of interneuronal and pyramidal cell populations (4.8 ms). In anesthetized rats, positive feedback gain coefficients were 0.07 among interneurons and 0.85 among pyramidal cells. After a compound spike (I), two postsynaptic AEP components (II and III) of different time courses were detectable at all depths within CA 1 except at the turnover for each component. The hypothesis that the AEP component II was generated by interneurons was tested and confirmed. The quantitative model constitutes a concise construct of the functional organization of the hippocampal CA 1 region, which suggests further theoretical extensions and experimentation.     

A model of cell firing patterns during epileptic seizures

A simplified model is presented of the dynamics of excitatory and inhibitory neurons in the cerebral cortex. A key feature of the model is that neurons may cease to fire when strongly depolarized (spike inactivation). Computer simulations for different parameters reveal five classes of solutons: a) steady states in which neither excitatory nor inhibitory cells are active, b) steady states in which one or both types of cells fire repetitively, c) states in which one type of cell fluctuates rapidly between bursts of action potentials and inactivity due to strong depolarization, d) rhythmic activity in which both types of cells fire in unison followed by a period of spike inactivation and e) states similar to d but in which the inhibitory cells never produce action potentials. Solutions b, c, d, and e qualitatively resemble the different firing patterns observed during experimental seizures. It is shown that changes in those parameters that are functions of potassium concentration can induce changes in the type of solution. It is therefore proposed that the increase in extracellular potassium concentration during seizures may be responsible for the progressive changes observed in firing patterns and particularly for the transition from tonic to clonic patterns. A method is also outlined for testing the predictions of the model.     

A model of feedback control for the charge-balanced suppression of epileptic seizures

Here we present several refinements to a model of feedback control for the suppression of epileptic seizures. We utilize a stochastic partial differential equation (SPDE) model of the human cortex. First, we verify the strong convergence of numerical solutions to this model, paying special attention to the sharp spatial changes that occur at electrode edges. This allows us to choose appropriate step sizes for our simulations; because the spatial step size must be small relative to the size of an electrode in order to resolve its electrical behavior, we are able to include a more detailed electrode profile in the simulation. Then, based on evidence that the mean soma potential is not the variable most closely related to the measurement of a cortical surface electrode, we develop a new model for this. The model is based on the currents flowing in the cortex and is used for a simulation of feedback control. The simulation utilizes a new control algorithm incorporating the total integral of the applied electrical potential. Not only does this succeed in suppressing the seizure-like oscillations, but it guarantees that the applied signal will be charge-balanced and therefore unlikely to cause cortical damage.     

On the prediction of epileptic seizures

In 12 epileptic patients suffering from absences 8-channel EEG was recorded by telemetry. The autoregressive model was applied to the signal and the prediction coefficients being the basis for calculation of the poles of the predictor. The location of the poles in thez- ands-planes was described as a function of time for 0.1 s steps along the pre-seizure EEG. In 10 of the 12 patients, and in 25 of the 28 recorded seizures this presentation of the poles of the predictor showed specific pattern linked with the occurrence of the siezure. The trajectory of the most mobile pole during the pre-seizure period could aid in the prediction of the seizure by several seconds.Dr. Isak Gath c/o Prof. Lehmann Neurologische Universitätsklinik CH-8091 Zürich Switzerland     

Inhibition modifies the effects of slow calcium-activated potassium channels on epileptiform activity in a neuronal network model

Generation of epileptiform activity typically results from a change in the balance between network excitation and inhibition. Experimental evidence indicates that alterations of either synaptic activity or intrinsic membrane properties can produce increased network excitation. The slow Ca²⁺-activated K⁺ currents (sI_AHP) are important modulators of neuronal firing rate and excitability and have important established and potential roles in epileptogenesis. While the effects of changes in sI_AHP on individual neuronal excitability are readily studied and well established, the effects of such changes on network behavior are less well known. The experiments here utilize a defined small network model of multicompartment pyramidal cells and an inhibitory interneuron to study the effects of changes in sI_AHP on network behavior. The benefits of this model system include the ability to observe activity in all cells in a network and the effects of interactions of multiple simultaneous influences. In the model with no inhibitory interneuron, increasing sI_AHP results in progressively decreasing burst activity. Adding an inhibitory interneuron changes the observed effects; at modest inhibitory strengths, increasing sI_AHP in all network neurons actually results in increased network bursting (except at very high values). The duration of the burst activity is influenced by the length of delay in a feedback loop, with longer loops resulting in more prolonged bursting. These observations illustrate that the study of potential antiepileptogenic membrane effects must be extended to realistic networks. Network inhibition can dramatically alter the observations seen in pure excitatory networks.     

Models of epileptic seizures in immature rats

Models of basic types of epileptic seizures are elaborated not only in adult but also in immature rodents. It is important because at least half of human epilepsies starts during infancy and childhood. This paper presents a review of chemically and electrically induced models of generalized convulsive and nonconvulsive (absence) seizures as well as models of partial simple (neocortical) and complex (limbic) seizures in immature rats. These models can also serve as a tool for study the development of central nervous system and motor abilities because the level of maturation is reflected in seizure semiology. Age-dependent models of epileptic seizures (absences and flexion seizures) are discussed. Models of seizures in immature animals should be used for testing of potential antiepileptic drugs.     

Role of oxidative stress in epileptic seizures

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetic rat models, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment.     

Clustering and coupled gating modulate the activity in KcsA, a potassium channel model

Different patterns of channel activity have been detected by patch clamping excised membrane patches from reconstituted giant liposomes containing purified KcsA, a potassium channel from prokaryotes. The more frequent pattern has a characteristic low channel opening probability and exhibits many other features reported for KcsA reconstituted into planar lipid bilayers, including a moderate voltage dependence, blockade by Na(+), and a strict dependence on acidic pH for channel opening. The predominant gating event in this low channel opening probability pattern corresponds to the positive coupling of two KcsA channels. However, other activity patterns have been detected as well, which are characterized by a high channel opening probability (HOP patterns), positive coupling of mostly five concerted channels, and profound changes in other KcsA features, including a different voltage dependence, channel opening at neutral pH, and lack of Na(+) blockade. The above functional diversity occurs correlatively to the heterogeneous supramolecular assembly of KcsA into clusters. Clustering of KcsA depends on protein concentration and occurs both in detergent solution and more markedly in reconstituted membranes, including giant liposomes, where some of the clusters are large enough (up to micrometer size) to be observed by confocal microscopy. As in the allosteric conformational spread responses observed in receptor clustering (Bray, D. and Duke, T. (2004) Annu. Rev. Biophys. Biomol. Struct. 33, 53-73) our tenet is that physical clustering of KcsA channels is behind the observed multiple coupled gating and diverse functional responses.     

EPR imaging for in vivo analysis of the half-life of a nitroxide radical in the hippocampus and cerebral cortex of rats after epileptic seizures.

Recently, we developed an in vivo temporal electron paramagnetic resonance (EPR) imaging technique to be applied to the brain of a rat, into which a blood-brain barrier (BBB)-permeable nitroxide radical, 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (PCAM) was injected intraperitoneally. This imaging technique made it possible to measure decay rates of a nitroxide radical in multiple regions of the brain simultaneously. Using this technique, the half-life of PCAM was estimated from the exponential decay of the signal intensity derived from the temporal EPR images in the hippocampus and cerebral cortex of rats after a kainic acid (KA)-induced seizure. The hippocampal half-life of PCAM after KA-induced seizures was significantly prolonged (p < .01), whereas the prolongation of the cortical half-life was not significant. These findings suggest that following a KA-seizure, the intrahippocampal ability to reduce the nitroxide radical is impaired, but the ability is intact in the cerebral cortex. This is the first in vivo quantitative EPR imaging study that has a bearing on the pathogenesis of KA-induced seizures in the brain.     

Cell-type specific depression of neuronal excitability in rat hippocampus by activation of ATP-sensitive potassium channels

The contribution of ATP-sensitive potassium (K(ATP)) channels to neuronal excitability was studied in different types of pyramidal cells and interneurones in hippocampal slices prepared from 9- to 15-day-old rats. The presence of functional K(ATP) channels in the neurones was detected through the sensitivity of whole-cell currents to diazoxide, a K(ATP) channel opener, and to tolbutamide, a K(ATP) channel inhibitor. The percentages of neurones with K(ATP) channels increase in the sequence: CA1 pyramidal cells (37%)相似文献   

The Wakayama epileptic rat (WER), a new mutant exhibiting tonic-clonic seizures and absence-like seizures.

A new mutant, the Wakayama epileptic rat (WER), exhibiting both spontaneous absence-like behavior and tonic-clonic convulsions, was identified in a colony of Wistar rats. To determine clear seizure characteristics of this mutant strain, we analyzed the mode of inheritance of the convulsion and observed patterns of electroencephalogram (EEG) during the seizures. F1 progeny were produced between the founder male and normal females of the same colony. Animals were monitored through the inbreeding course to analyze genetic control of epileptic behavior. EEGs were recorded using affected animals in the F3-4 and post F13 generations. After the F2 generation, affected rats spontaneously exhibited both absence-like immobile behavior and tonic-clonic convulsions. The absence-like seizures were characterized by motor arrest and head droop. The tonic-clonic convulsions began with neck and forelimb clonus, wild jumping/running, and opisthotonic posturing, and evolved to tonic, then clonic convulsions. Most convulsion onsets occurred between 25-70 days of age. Mating experiments revealed that 0%(0/18) of the animals in F1, 10%(3/26) in F2, 17%(1/6) in backcross progeny and 86% (100/116) in progeny of crosses between epileptic rats showed tonic-clonic convulsions. Ictal cortical EEGs were characterized by 4-6 (5.1 +/- 0.4, mean +/- SD) Hz spike-and-wave complexes in the absence-like seizures and by low-voltage fast waves in the tonic-clonic convulsions. This new mutant rat spontaneously exhibited both absence-like and tonic-clonic seizures. The tonic-clonic seizure was inherited as an autosomal recessive trait with 86% incidence. Thus, the new mutant rat may become a useful model for studying human inherited epilepsies.     

The neuronal influence on tumor progression

Nerve fibers accompany blood and lymphatic vessels all over the body. An extensive amount of knowledge has been obtained with regard to tumor angiogenesis and tumor lymphangiogenesis, yet little is known about the potential biological effects of "neoneurogenesis". Cancer cells can exploit the advantage of the factors released by the nerve fibers to generate a positive microenvironment for cell survival and proliferation. At the same time, they can stimulate the formation of neurites by secreting neurotrophic factors and axon guidance molecules. The neuronal influence on the biology of a neoplasm was initially described several decades ago. Since then, an increasing amount of experimental evidence strongly suggests the existence of reciprocal interactions between cancer cells and nerves in humans. Moreover, researchers have been able to demonstrate a crosstalk between cancer cells and nerve fibers as a strategy for survival. Despite all these evidence, a lot remains to be done in order to clarify the role of neurotransmitters, neuropeptides, and their associated receptor-initiated signaling pathways in the development and progression of cancer, and response to therapy. A global-wide characterization of the neurotransmitters or neuropeptides present in the tumor microenvironment would provide insights into the real biological influences of the neuronal tissue on tumor progression. This review is intended to discuss our current understanding of neurosignaling in cancer and its potential implications on cancer prevention and therapy. The review will focus on the soluble factors released by cancer cells and nerve endings, their biological effects and their potential relevance in the treatment of cancer.     

An influence of methane concentration on the methanotrophic activity of a model landfill cover

Evaluation of kinetic parameters of methane oxidation under various conditions, on the basis of an analysis of the literature and the authors’ own laboratory research, is presented. Variation in methanotrophic activity in the profile of a simulated landfill cover was observed. The greatest activity was found at a depth of 60 cm. A low affinity (1/K_M) and high potential activity (V_max) were observed. V_max values ranged from 0.11 × 10⁻³ to 0.86 × 10⁻³ units. The values of K_M ranged from 0.6 to 2.9% of CH₄ (v/v).     

The role of trace elements in the pathogenesis and progress of pilocarpine-induced epileptic seizures

X-ray fluorescence microscopy was applied for topographic and quantitative elemental analysis within the areas of the rat brain that undergo neurodegenerative changes in consequence of pilocarpine-induced seizures. Significant changes in levels of selected elements were observed in epileptic animals. They included an increased tissue content of Ca in the CA1 and CA3 regions of the hippocampus and in the cerebral cortex. The opposite relation was observed for the Cu level in the dentate gyrus and for Zn in the CA3 region of the hippocampus and in the dentate gyrus.     

The selective inhibition of hippocampal glutamic acid decarboxylase in zinc-induced epileptic seizures

The intracerebroventricular administration of Zn²⁺ (0.3 mol/10 l) causes epileptic seizures characterized by running fits, jumping, vocalization, fasiculation of facial muscles, myoclonic movements of the limbs and tonic-clonic convulsions. These episodes are blocked or reversed by -aminobutyric acid (0.4 mol/10 l). When assayed under conditions where pyridoxal phosphate was not added, the activity of glutamic acid decarboxylase decreased significantly in hippocampus from 18.9 to 15.3 and 9.7 mol¹⁴CO₂ formed/gram proteins/20 min, 15 and 30 min following administration of Zn²⁺. The inhibition of glutamic acid decarboxylase by Zn²⁺ was selective occurring only in hippocampus and not in the hypothalamus, amygdala, caudate or thalamus. The inhibition of glutamic acid decarboxylase was not due to a reduction in the concentration of endogenous pyridoxal phosphate which remained unaltered in hippocampus following Zn²⁺ administration.