Fentanyl treatment reduces GABAergic inhibition in the CA1 area of the hippocampus 24 h after acute exposure to the drug.

The effect of in vivo fentanyl treatment on synaptic transmission was studied in the CA1 area of the rat hippocampus. Animals were treated either with saline or fentanyl (4 x 80 microg/kg, s.c./15 min). Intracellular in vitro recordings were obtained, 24 h after treatment, from CA1 pyramidal neurons. No difference in pyramidal neuron basic membrane properties or postsynaptic membrane excitability was observed between neurons from saline- and fentanyl-treated animals. The peak amplitude of fast (f-) and slow (s-) components of IPSPs elicited in standard ACSF and the peak amplitude and rate of rise of isolated f- and s-IPSPs elicited in the presence of antagonists (CNQX, 10 microM; AP-5, 10 microM; CGP 55845, 1 microM; and bicuculline methochloride, 10 microM), in response to various stimulus intensities, was smaller in fentanyl-treated animals. Conversely, the rising slope of excitatory responses was similar in neurons from saline- and fentanyl-treated animals. Furthermore, in fentanyl-treated animals, lower stimulus strengths were required to elicit subthreshold excitatory responses of the same amplitude suggesting that acute exposure to fentanyl increases susceptibility of pyramidal neurons to presynaptic stimulation. GABA immunohistochemistry revealed lower GABA content in processes and neuronal somata suggesting diminished GABA release onto pyramidal neurons. We conclude that acute in vivo exposure to fentanyl is sufficient to induce long-lasting reduction in GABA-mediated transmission, rather, than enhanced excitatory transmission or modulation of the intrinsic excitability of pyramidal neurons. These findings provide evidence regarding the mechanisms involved in the early stages of tolerance development towards the analgesic effects of opioids.

Exploring the variability of single trials in somatosensory evoked responses using constrained source extraction and RMT.

This paper describes the theoretical background of a new data-driven approach to encephalographic single-trial (ST) data analysis. Temporal constrained source extraction using sparse decomposition identifies signal topographies that closely match the shape characteristics of a reference signal, one response for each ST. The correlations between these ST topographies are computed for formal Correlation Matrix Analysis (CMA) based on Random Matrix Theory (RMT). The RMT-CMA provides clusters of similar ST topologies in a completely unsupervised manner. These patterns are then classified into deterministic set and noise using well established RMT results. The efficacy of the method is applied to EEG and MEG data of somatosensory evoked responses (SERs). The results demonstrate that the method can recover brain signals with time course resembling the reference signal and follow changes in strength and/or topography in time by simply stepping the reference signal through time.

Greater contribution of N-methyl-D-aspartic acid receptors in ventral compared to dorsal hippocampal slices in the expression and long-term maintenance of epileptiform activity.

Functional segregation along the dorso-ventral axis of the hippocampus is a developing concept. The higher susceptibility of the ventral hippocampus to epileptic activity compared with dorsal hippocampus is one of the main features, which still has obscure mechanisms. Using the model of magnesium-free medium and field recordings, single epileptiform discharges displayed higher incidence (77% vs 57%), rate (41.7+/-3.1 vs 13.5+/-0.7 events/min), duration (173.9+/-17.7 vs 116.8+/-13.6 ms) and intensity (coastline, 25.4+/-2.5 vs 9.5+/-1.8) in ventral compared with dorsal rat hippocampal slices. In addition, the decay phase of the evoked synaptic potentials was 110% slower in ventral slices. The N-methyl-D-aspartate (NMDA) receptor antagonist d-(-)-2-amino-5-phosphonopentanoic acid (50-100 microM) decreased the discharge rate and coastline similarly in ventral and dorsal slices, but it shortened the discharges in ventral slices (by 40%) only. The NMDA receptor antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (10 microM) decreased the rate in both groups and additionally shortened discharges in both kinds of slices, an effect which was greater in ventral ones (31% vs 13%). Furthermore, both drugs shortened the evoked potentials more in ventral (77%) than in dorsal slices (52%). On the other hand, 1 microM of 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid shortened the discharges and evoked synaptic potentials only in ventral slices, and slowed down the discharge rate only in dorsal slices. Addition of NMDA, in the magnesium-free medium, enhanced activity in both kinds of slices. At 5 and 10 microM of NMDA 51% of the ventral but only 9% of the dorsal slices displayed persistent epileptiform discharges, which were recorded for at least one hour after reintroduction of magnesium in the medium. At 10-20 microM the enhancement of activity was transient, followed by suppression of discharges in 40% and 76% of the ventral and dorsal slices, respectively. Most of the slices having experienced suppression did not develop persistent activity. We propose that the NMDA receptors contribute to the higher susceptibility of the ventral hippocampus to expression and long-term maintenance of epileptiform discharges. This diversification may be related to other aspects of hippocampal dorso-ventral functional segregation.

Vascular network of the rat hippocampus is not homogeneous along the septotemporal axis.

Qualitative and quantitative image analysis of hippocampal vascular bed, after transcardial perfusion of India ink, reveals significant differences among hippocampal subfields and along the septotemporal axis of the rat hippocampus. Ventral hippocampus exhibits significantly higher levels of vascularization compared to dorsal hippocampus, which, however, is characterized by significantly higher capillary density. These results may explain the selective ischemia vulnerability of hippocampus along its septotemporal axis.

Bronchogenic cyst infected by Salmonella enteritidis followed gastroenteritis.

Congenital bronchogenic cysts of the lung and mediastinum develop from the ventral foregut during embryogenesis. Bronchogenic cysts are seldom seen in the adults and most are thought to be asymptomatic and free of complications unless they become infected or are large enough to cause pressure on contiguous vital structures such as the tracheal carina, the lung or the esophagus. We present the unique case of a 24-year-old man who developed respiratory symptoms after Salmonella enteritidis infected bronchogenic cyst following Salmonella gastroenteritis.

Involvement of the thalamocortical system in epileptic loss of consciousness.

Experiments on putative neuronal mechanisms underlying absence seizures as well as clinical observations are critically reviewed for their ability to explain apparent "loss of consciousness." It is argued that the initial defect in absences lies with corticothalamic (CT) neuronal mechanisms responsible for selective attention and/or planning for action, rather than with those establishing either the states or the contents of consciousness. Normally, rich thalamocortical (TC)-CT feedback loops regulate the flow of information to the cortex and help its neurons to organize themselves in discrete assemblies, which through high-frequency (>30 Hz) oscillations bind those distributed processes of the brain that are considered important, so that we are able to focus on what is needed from moment to moment and be aware of this fact. This ability is transiently lost in absence seizures, because large numbers of CT loops are recruited for seconds in much stronger, low-frequency ( approximately 3 Hz) oscillations of EPSP/IPSP sequences, which underlie electroencephalographic (EEG) spike-and-wave discharges (SWDs). These oscillations probably result from a transformation of the normal EEG rhythm of sleep spindles on an abnormal increase of cortical excitability that results in strong activation of inhibitory neurons in the cortex and in nucleus reticularis thalami. The strong general enhancement of CT feedback during SWDs may disallow the discrete feedback, which normally selects specific TC circuits for conscious perception and/or motor reaction. Such a mechanism of SWD generation allows variability in the extent to which different TC sectors are engaged in the SWD activity and thus explains the variable ability of some patients to respond during an absence, depending on the sensory modality examined.

Modeling of evoked field potentials in hippocampal CA1 area describes their dependence on NMDA and GABA receptors.

A computer model of the hippocampal CA1 area, which receives synaptic inputs from CA3 neurons via the Schaffer collaterals, was constructed. Pyramidal cells (PC) and two types of interneurons were represented by compartmental models, and mechanisms of feed-forward inhibition (FFI) and recurrent inhibition were incorporated. Four types of receptor mediated synaptic conductances were used in the model: those of AMPA, GABA(A), GABA(B) and N-methyl-D-aspartate (NMDA). The output of the model, i.e. the field potential calculated at various points in space, was able to qualitatively reproduce the main features of field potentials, which were recorded in hippocampal slices maintained in vitro for both subthreshold and suprathreshold stimulation. In both the experiments and the model, the influence of NMDA and GABA synaptic currents affected mostly the late, decaying phase of evoked field potentials. The modeled interaction of NMDA and GABA components could explain the enhancement of the field potential late phase, which was observed experimentally during paired-pulse stimulation.

Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: the continuing development of a hypothesis.

OBJECTIVES: This review aims to offer a critical account of recent scientific developments relevant to the hypothesis which Pierre Gloor proposed in the 1970s for the generation of spike and wave discharges (SWDs) of primary generalized absence seizures. RESULTS: According to this hypothesis SWDs develop in the same circuits, which normally generate sleep spindles, by an initially cortical transformation of one every two or more spindle waves to a 'spike' component of SWDs, while the next one or more spindle waves are eliminated and replaced by a slow negative wave. This hypothesis was based on experiments in feline generalized penicillin epilepsy showing the possibility of transition from spindles to SWDs, when cortical neurons become hyper-responsive to thalamocortical volleys, which normally induce spindles, and thus engage feedback cortical inhibition, rebound excitation, recurrent intracortical dissemination of excitation during the 'spike' and strong excitation of thalamus for further augmentation of a brain wide synchronous oscillation. In the 1980s, electrophysiological studies in vitro and in vivo revealed the basic features of spindle rhythm generation by neurons in nucleus reticularis thalami and thalamocortical-corticothalamic oscillatory reverberations. CONCLUSIONS: In the light of this knowledge, experimental studies in several genetic and pharmacological animal models of absence seizures, clinical observations and theoretical studies in computer models have considered, tested, modified and challenged this hypothesis. It may still be found useful in the era of dynamic digital EEG analysis of SWDs and its current sources.

Dorsal-ventral differentiation of short-term synaptic plasticity in rat CA1 hippocampal region.

Two forms of short-term synaptic plasticity (STP), paired-pulse facilitation (PPF) and frequency potentiation (FP) of CA1 field excitatory postsynaptic potentials (EPSP) to afferent stimulation were compared in slices taken from the dorsal and ventral parts of rat hippocampus. While dorsal slices showed significant PPF at all interpulse intervals (20-1400 ms, 80% at 40 ms), PPF in ventral slices was substantially weaker at intervals shorter than 100 ms (19% at 40 ms) and nil at longer intervals. While dorsal slices showed substantial FP at frequencies 1-40 Hz and frequency depression at 50-100 Hz, ventral slices showed only a much smaller potentiation at 1 Hz and substantial depression at 20-100 Hz. Decreasing [Ca(2+)](o) from 2 to 1 and 0.5 mM substantially reduced the baseline EPSPs in both groups of slices but its effect on PPF was greater in ventral slices. On the contrary when [Ca(2+)](o) was increased to 5 mM only dorsal slices showed an enhancement of baseline EPSP. It is concluded that ventral hippocampus CA1 area has a specific deficit in STP, which is related to the important presynaptic role of calcium and is consistent with a relatively higher transmitter release probability.

Reduction of A1 adenosine receptors in rat hippocampus after kainic acid-induced limbic seizures.

In a temporal lobe epilepsy (TLE) model induced by kainic acid (KA), we examined the effect of limbic seizures on A1 adenosine receptor distribution in hippocampus and cortex. By using quantitative autoradiography, we determined a progressive decrease in A1 receptor density in CA1 and CA3 regions of hippocampus, which coincided in time with the degenerating process of hippocampal pyramidal cells. This result indicates that a great amount of A1 receptors are located postsynaptically on pyramidal cell dendrites. No difference in A1 receptor density was observed in the inner compared to the outer molecular layer of dentate gyrus, or in the infrapyramidal band compared to the outer layer of stratum oriens of CA3. This could indicate that the newly sprouted mossy fiber glutamatergic terminals do not contain A1 receptors, thus lacking a restrain in the release of glutamate.

Decreased ability of rat temporal hippocampal CA1 region to produce long-term potentiation.

Tetanic stimulation of Schaffer collaterals in the CA1 region of transverse slices, taken from the septal (dorsal) part of young rat hippocampus, produced N-Methyl-D-aspartate-dependent long-term potentiation (LTP) of the rising slope of excitatory postsynaptic potential (mean 38%). Under identical conditions of stimulation (100 Hz, 1 s) slices taken from the temporal (ventral) third of hippocampus presented a substantially reduced ability for LTP (mean 5%). The defect appeared to lie with the induction rather than the maintenance phase of LTP. These results suggest that a significant functional differentiation at the local synaptic plasticity level occurs between the two poles of hippocampus, which together with the substantial differences in their extrinsic connections, may help explain the reported differential participation of neurons in these parts of hippocampus during animal memory tests.

Development of a transient increase in recurrent inhibition and paired-pulse facilitation in hippocampal CA1 region.

Paired-pulse recurrent inhibition (RI) of population spike (PS) and facilitation (PPF) of field excitatory postsynaptic potential (EPSP) were studied in the CA1 region of hippocampal slices taken from Wistar rats aged from 9 days to 16 months. The comparison of three different paired-pulse protocols revealed the antidromic-orthodromic (A-O) stimulation as the most reliable in quantifying the strength of fast (peaking at 10 ms) and slow (peaking at 200 ms) components of recurrent inhibition. Fast RI, present but weak at 9 days, progressively increased to reach its maximal strength at 30 days, declining in adult (2 m) and middle-aged (16 m) animals. Slow RI was replaced by facilitation at 9 days while it was absent at 15 days. It reached adult values at 30 days. A reduction of the test response at interpulse interval (IPI) of 2-4 ms was strong in developing and adult animals, but was significantly decreased in 16 m. At maximal stimulation PPF was expressed as an enhancement of the slow rather than the fast phase of the EPSP and was particularly strong with a prominent N-methyl-D-aspartate dependent component. A very characteristic selectivity for a prominent PPF at stimulation frequency of 5 Hz appeared first at the 18th day and increased gradually to reach a maximum at the 30th day, after which it declined to very low values in middle-aged animals. A similar developmental pattern was observed in slices taken from rats reared in complete darkness, suggesting a strong innate origin. The ability of hippocampal circuits for plastic gating of information appears to be transiently enhanced at the completion of the first postnatal month as it can be exercised at a wider part of the frequency spectrum, with maximal inhibition and potentiation especially at the frequency of theta rhythm.

Lower density of A1 adenosine receptors in nucleus reticularis thalami in rats with genetic absence epilepsy.

The possible involvement of the adenosinergic modulatory system in the pathogenesis of absence seizures was investigated in genetic absence epilepsy rats from Strasbourg (GAERS). Using in vitro quantitative autoradiography, the distribution of A1 adenosine receptors and adenosine uptake sites in the brain of GAERS was studied and compared to that of control animals. An area-specific lower density of A1 receptors (15% decrease) was detected in reticular (nRT) and anterior ventral (AV) thalamic nuclei as well as basal ganglia in the brains of GAERS animals compared with control animals. Since adenosine exerts an anti-oscillatory effect on the thalamic nuclei by suppressing (via A1 receptors) excitatory as well as inhibitory neurotransmitter release, the impairment in A1 receptor density seen here, especially in nRT, could be implicated in the thalamic rhythmicity underlying spike and wave discharges present in this absence epilepsy model.

Novel approach to a quantitative treatment of the quantal transmitter release at the frog neuromuscular junction.

To explain the discrepancy between estimates of parameters of quantal transmitter release received by different techniques the paper postulates a novel concept for quanta mobilization, which assumes that a quantum emitted by a vesicle transiently acquires a transition state in which it is immediately available for release. The working particle model is formulated in terms of probabilities of inter-state quanta transitions. The parameters of the model are determined by fitting solutions to the experimental curves representing short-term changes of synaptic efficacy at the frog neuromuscular junction as well as taking into account the morphologically estimated number of releasable vesicles. The value of the model is demonstrated by successful prediction of the estimates of the parameters of the quantal transmitter release suggested by evidence received from different lines of research.

Age-related changes in excitability and recurrent inhibition in the rat CA1 hippocampal region.

In hippocampal slices from male Wistar rats aged 1-34 months, we recorded the synaptic field potential responses of the CA1 neurons to stimulation of Schaffer collaterals. Eight electrophysiological indexes were extracted from input/output curves and compared in 11 age groups from 1 to 30 months. Neuronal excitability presented a U-shaped curve of development with a minimum at approximately 7-8 months of age. There was a significant continuous increase in neuronal excitability, i.e. a decrease in excitatory postsynaptic potential (EPSP) producing both the threshold and half-maximal population spike from middle age (8-10 months) to senescence (30 months). Synaptic efficiency also increased in old rats to reach a maximum during senescence, i.e. both the current for threshold EPSP and that for half-maximal EPSP reached a minimum in senescence, although the earlier developmental patterns of these two indexes were non-linear. The duration of the field EPSP elicited with maximal stimulation presented an abrupt decay after the first month. Aged animals presented a relatively small maximal population spike. Recurrent inhibition was most prominent on neuronal excitability rather than synaptic strength. Measured as the percentage change in the half-maximal EPSP and half-maximal population spike, recurrent inhibition was found to decrease during the first 7-10 months of life and remained small in later development.

Stochastic particle formulation of the vesicle hypothesis. Relevance to short-term phenomena.

Based on the vesicle hypothesis, the modes of elementary quantum-vesicle interactions have been formulated in terms of probabilities of induced and spontaneous interstate quanta transitions and generalized within the framework of the previously developed theory of the double barrier synapse. Among the three allowed states for a quantum, the transition state is a novel formulation for the fraction of immediately available quanta governed by both vesicle and presynaptic membranes. The parameters of the model were determined by fitting solutions to the experimental curves representing effects of single pulse and short train activation on transmitter release at the frog neuromuscular junction. Qualitative differences in particle physics of transmitter release found under low quantal outputs on one hand and normal transmission on the other allowed the formulation of the uncertainty hypothesis and the quantum condition of synaptic homeostasis.

Simulation study for the transition from spindles to spike and wave epileptogenesis.

A mathematical model is presented, based on existing anatomical and physiological data, which simulates the behaviour of representative types of cortical cells. It is used to test whether a set of synaptic connections of these cells exists, which, paced by the same rhythmical thalamic input, could produce spindles under normal conditions and spike and wave discharges (SW) under conditions of cortical hyperexcitability. This is possible if the interneurons do not provide recurrent excitatory or inhibitory input on themselves, if the thalamic afferents contact the cortical projecting pyramidal cells through local excitatory neurons, and if the inhibitory interneurons receive input only from the pyramidal cells. The results suggest that an increase of all cortical synaptic actions (both excitatory and inhibitory) is sufficient for the transition from spindles to the first stages in the development of SW discharges in the cortex, whereas the thalamus can be driven to the SW characteristic frequency at the immediate next stages.

Pentylenetetrazol-induced seizures decrease gamma-aminobutyric acid-mediated recurrent inhibition and enhance adenosine-mediated depression.

To elucidate the consequences of convulsions, we examined biochemically and electrophysiologically the brains of mice that had sustained two complete tonic-clonic convulsions after administration of pentylenetetrazol (PTZ 50 mg/kg intraperitoneally, i.p.), 48 and 24 h before decapitation. Control mice were injected with saline. Input/output curves of the extracellular synaptic responses in the CA1 area of hippocampal slices showed that PTZ-induced seizures do not establish the persistent change in hippocampal excitability itself that can be detected in vitro. However, use of the paired-pulse stimulation paradigm showed that gamma-aminobutyric acid A (GABAA)-mediated recurrent inhibition was significantly weaker (by 19-25%) in the CA1 area of slices from PTZ-treated mice (PTZ slices) as compared with slices from control mice (control slices). The density of GABAA receptors (high-affinity component) was also lower in hippocampus (by 19%) and cortex (by 14%) of PTZ-treated mice. A GABA-related disinhibitory mechanism underlying PTZ seizures may thus persist for 1 day after the seizure, predisposing the brain to subsequent seizures. On the other hand, the depressant effect of a single dose of adenosine 10 microM on the CA1 synaptic response was stronger (by 35% on population spikes) and longer lasting in PTZ slices as compared with controls. This could be attributed to significantly higher adenosine A1 receptor density in hippocampus (Bmax of [3H]CHA was higher by 34%) as well as cortex and cerebellum of these animals. The phenomenon may reflect an adenosine A1-mediated adaptive mechanism that offers protection from subsequent seizures.

Upregulation of A1 adenosine receptors in human temporal lobe epilepsy: a quantitative autoradiographic study.

A significant increase of A1 adenosine receptor binding (48% increase of mean) was detected in human neocortex obtained from patients suffering from temporal lobe epilepsy as compared to control neocortex from non-epileptic patients. Such increase was equally distributed in the six cortical layers and reached similar levels in each of the five specimens tested independently of age, sex and pharmacological treatment of the patient. Since adenosine exerts a depressant effect on neocortical neurons in slices obtained from epileptic patients, this upregulation of A1 receptor binding may constitute a protective mechanism against subsequent seizures, which is exerted by elevating the depressant response of the brain to endogenous adenosine.

Effect of pentylentetrazol-induced seizures on A1 adenosine receptor regional density in the mouse brain: a quantitative autoradiographic study.

Adenosine has been shown to be a major regulator of neuronal activity in convulsive disorders, exerting its anticonvulsant effect through central A1 adenosine receptors. The aim of the present study was to investigate the effect of generalized tonic-clonic seizures induced by pentylentetrazol on regional changes in A1 adenosine receptor density and distribution in the mouse brain by in vitro quantitative autoradiography. As radioligand the specific agonist of A1 receptors [3H]cyclohexyladenosine was used. After two consecutive (once daily) pentylentetrazol-induced convulsions a widespread upregulation of A1 receptor density was detected with a marked enhancement in structures that mediate seizure activity like hippocampus, mamillary bodies, septum, substantia nigra, thalamic nuclei and cerebral cortices. On the contrary, in basal ganglia a significant downregulation of A1 receptors was observed. These results indicate that: (i) the observed increases or decreases in A1 receptor density are organized in selective anatomical structures related to seizure development rather than uniform in the brain; and (ii) since the upregulation of A1 receptors is sufficient to enhance the physiological depressive response of adenosine, the overall evoked increases seen here may lead to a stronger inhibitory tone and accordingly to a more efficient anticonvulsant effect of endogenous adenosine.