Spontaneous Burst Discharges Research Articles

On a unified point process approach for the characterization of bioelectric discrete phenomena.

This paper discusses a unified method based on the theory of point processes to characterize various types of bioelectric discrete signals such as heart beat timing, myoelectric activity, discharge of primary sensory neurons or neurons in the central nervous systems. The doubly stochastic point processes, in which the discrete event occurring intensity is stochastic, forms the most general class to characterize the discrete phenomena. In this paper the self-exciting process has been shown to be useful to characterize wide range of discrete biosignals. The modeling of conditional intensity function is the essential part of the characterization. When the intensity has a parametric model, the maximum likelihood parameter estimation will be the useful way to characterize the phenomena. The effectiveness of the method is demonstrated by a specific modeling of the spontaneous neuronal burst discharges recorded from the brain thalamus during the neuro surgery. The first approximation model has four parameters obtained by the instantaneous nonlinearly transformed sinusoidal function. An extended model allows arbitrary periodic intensity with refractory period. Predicted interval histograms show good agreement with the observed ones indicating the validity of the proposed method.

The immunosuppressant cyclosporin A inhibits recurrent seizures in an experimental model of temporal lobe epilepsy

The immunosuppressant, cyclosporin A (CsA), is neuroprotective following brain injury. Previous studies suggest that CsA treatment ameliorates seizure severity during status epilepticus (SE) or cell death following SE. The antiepileptic effects of CsA on recurrent seizures, however, have not been investigated. In the present study, the effects of CsA on spontaneous recurrent seizures (SRSs) in a kainate (KA)-induced mouse model of mesial temporal lobe epilepsy (TLE) were examined. Moreover, the effects of CsA on epileptiform activity in a 4-aminopyridine (4-AP)-induced in vitro seizure model were investigated. A mesial TLE mouse model was generated with a unilateral intrahippocampal injection of KA. SRSs were determined in the ipsilateral hippocampal CA1 region with a long-term video-EEG. CsA was systemically administrated to the epileptic mice exhibiting a stable occurrence of SRSs. A 1-mg/kg dose of CsA did not have any effect on SRSs in the epileptic mice. However, a 5-mg/kg dose of CsA significantly reduced the number of SRSs and decreased the severity of the seizures in the epileptic mice. Additionally, CsA treatment inhibited spontaneous burst discharges in 4-AP-treated hippocampal slices. The results of the present study demonstrate that CsA inhibits recurrent seizures in a mouse model of mesial TLE and suggest that CsA may afford both neuroprotection against SE and antiepileptic effects during the chronic period of epilepsy.

No phylogeny without ontogeny — a comparative and developmental search for the sources of sleep-like neural and behavioral rhythms

A comprehensive review is presented of reported aspects and putative mechanisms of sleep-like motility rhythms throughout the animal kingdom. It is proposed that 'rapid eye movement (REM) sleep' be regarded as a special case of a distinct but much broader category of behavior, 'rapid body movement (RBM) sleep', defined by intrinsically-generated and apparently non-purposive movements. Such a classification completes a 2 × 2 matrix defined by the axes sleep versus waking and active versus quiet. Although 'paradoxical' arousal of forebrain electrical activity is restricted to warm-blooded vertebrates, we urge that juvenile or even infantile stages of development be investigated in cold-blooded animals, in view of the many reports of REM-like spontaneous motility (RBMs) in a wide range of species during sleep. The neurophysiological bases for motorically active sleep at the brainstem level and for slow-wave sleep in the forebrain appear to be remarkably similar, and to be subserved in both cases by a primitive diffuse mode of neuronal organization. Thus, the spontaneous synchronous burst discharges which are characteristics of the sleeping brain can be readily simulated even by highly unstructured neural network models. Neuromotor discharges during active sleep appear to reflect a hierarchy of simple relaxation oscillation mechanisms, spanning a wide range of spike-dependent relaxation times, whereas the periodic alternation of active and quiet sleep states more likely results from the entrainment of intrinsic cellular rhythms and/or from activity-dependent homeostatic changes in network excitability.

Changes of paired-pulse evoked responses during the development of epileptic activity in the hippocampus

Dysfunction of inhibitory synaptic transmission can destroy the balance between excitatory and inhibitory synaptic inputs in neurons, thereby inducing epileptic activity. The aim of the paper is to investigate the effects of successive excitatory inputs on the epileptic activity induced in the absence of inhibitions. Paired-pulse orthodromic and antidromic stimulations were used to test the changes in the evoked responses in the hippocampus. Picrotoxin (PTX), γ-aminobutyric acid (GABA) type A (GABA(A)) receptor antagonist, was added to block the inhibitory synaptic transmission and to establish the epileptic model. Extracellular evoked population spike (PS) was recorded in the CA1 region of the hippocampus. The results showed that the application of PTX induced a biphasic change in the paired-pulse ratio of PS amplitude. A short latency increase of the second PS (PS2) was later followed by a reappearance of PS2 depression. This type of depression was observed in both orthodromic and antidromic paired-pulse responses, whereas the GABAergic PS2 depression [called paired-pulse depression (PPD)] during baseline recordings only appeared in orthodromic-evoked responses. In addition, the depression duration at approximately 100 ms was consistent with a relative silent period observed within spontaneous burst discharges induced by prolonged application of PTX. In conclusion, the neurons may ignore the excitatory inputs and intrinsically generate bursts during epileptic activity. The depolarization block could be the mechanisms underlying the PPD in the absence of GABA(A) inhibitions. The distinct neuronal responses to stimulations during different epileptic stages may implicate the different antiepileptic effects of electrical stimulation.

Physiological identification of the human pedunculopontine nucleus

Background:The pedunculopontine nucleus (PPN) is a brainstem structure with widespread connections to the basal ganglia. Despite the recent introduction of PPN deep brain stimulation (DBS) for the treatment of gait...

Cellular and Network Mechanisms of Operant Learning-Induced Compulsive Behavior in Aplysia

Learning in exploratory and goal-directed behaviors can modify decision-making processes in the initiation of appropriate action and thereby transform the irregular and infrequent expression of such behaviors into inflexible, compulsive-like repetitive actions. However, the neuronal mechanisms underlying such learning-derived behavioral plasticity remain poorly understood. Appetitive operant conditioning, a form of associative learning, produces a long-lasting switch in the mollusk Aplysia's food-seeking behavior from irregular, impulsive-like radula biting movements into stereotyped, compulsive-like recurrences of this cyclic act. Using isolated buccal ganglia, we recorded intracellularly from an electrically coupled subset of feeding-network neurons whose spontaneous burst discharge is responsible for instigating the motor pattern underlying each radula bite cycle. We report that the sporadic production of biting patterns in preparations from naive and noncontingently trained animals derives from the inherently variable and incoherent bursting of these pattern-initiating neurons that are each randomly capable of triggering a given bite. However, the accelerated rhythmically recurring expression of radula motor patterns after contingent-reward training in vivo arises from a regularization and synchronization of burst discharge in the pattern-initiating cells through a promotion of stereotyped burst-generating oscillations and an increase in the strength of their electrical coupling. Our results show that plasticity in the spatiotemporal organization of pacemaker bursting, both within and between components of an action-initiating neuronal subcircuit, provides novel cellular substrates by which operant learning alters the recurrent expression of a simple goal-directed behavior.

Functional stabilization of weakened thalamic pacemaker channel regulation in rat absence epilepsy

Aberrant function of pacemaker currents (Ih), carried by hyperpolarization-activated cation non-selective (HCN) channels, affects neuronal excitability and accompanies epilepsy, but its distinct roles in epileptogenesis and chronic epilepsy are unclear. We probed Ih function and subunit composition during both pre- and chronically epileptic stages in thalamocortical (TC) neurones of the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Voltage gating of Ih was unaltered in mature somatosensory TC cells, both in vivo and in vitro. However, the enhancement of Ih by phasic, near-physiological, cAMP pulses was diminished by approximately 40% and the half-maximal cAMP concentration increased by approximately 5-fold. This decreased responsiveness of Ih to its major cellular modulator preceded epilepsy onset in GAERS, persisted throughout the chronic state, and was accompanied by an enhanced expression of the cAMP-insensitive HCN1 channel mRNA (> 50%), without changes in the mRNA levels of HCN2 and HCN4. To assess for alterations in TC cell excitability, we monitored the slow up-regulation of Ih that is induced by Ca2+-triggered cAMP synthesis and important for terminating in vitro synchronized oscillations. Remarkably, repetitive rebound Ca2+ spikes evoked normal slow Ih up-regulation in mature GAERS neurones; that sufficed to attenuate spontaneous rhythmic burst discharges. These adaptive mechanisms occurred upstream of cAMP turnover and involved enhanced intracellular Ca2+ accumulation upon repetitive low-threshold Ca2+ discharges. Therefore, HCN channels appear to play a dual role in epilepsy. Weakened cAMP binding to HCN channels precedes, and likely promotes, epileptogenesis in GAERS, whereas compensatory mechanisms stabilizing Ih function contribute to the termination of spike-and-wave discharges in chronic epilepsy.

Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D‐deficient mice

Although of clinical importance, little is known about the mechanism of seizure in neuronal ceroid lipofuscinosis (NCL). In the present study, we have attempted to elucidate the mechanism underlying the seizure of cathepsin D-deficient (CD-/-) mice that show a novel type of lysosomal storage disease with a phenotype resembling late infantile NCL. In hippocampal slices prepared from CD-/- mice at post-natal day (P)24, spontaneous burst discharges were recorded from CA3 pyramidal cells. At P24, the mean amplitude of IPSPs after stimulation of the mossy fibres was significantly smaller than that of wild-type mice, which was substantiated by the decreased level of gamma-aminobutyric acid (GABA) contents in the hippocampus measured by high-performance liquid chromatography (HPLC). At this stage, activated microglia were found to accumulate in the pyramidal cell layer of the hippocampal CA3 subfield of CD-/- mice. However, there was no significant change in the numerical density of GABAergic interneurons in the CA3 subfield of CD-/- mice at P24, estimated by counting the number of glutamate decarboxylase (GAD) 67-immunoreactive somata. In the hippocampus and the cortex of CD-/- mice at P24, some GABAergic interneurons displayed extremely high somatic granular immunoreactivites for GAD67, suggesting the lysosomal accumulation of GAD67. GAD67 levels in axon terminals abutting on to perisomatic regions of hippocampal CA3 pyramidal cells was not significantly changed in CD-/- mice even at P24, whereas the total protein levels of GAD67 in both the hippocampus and the cortex of CD-/- mice after P24 were significantly decreased as a result of degradation. Furthermore, the recombinant human GAD65/67 was rapidly digested by the lysosomal fraction prepared from the whole brain of wild-type and CD-/- mice. These observations strongly suggest that the reduction of GABA contents, presumably because of lysosomal degradation of GAD67 and lysosomal accumulation of its degraded forms, are responsible for the dysfunction of GABAergic interneurons in the hippocampal CA3 subfield of CD-/- mice.

β1 Adrenergic Receptor-Mediated Enhancement of Hippocampal CA3 Network Activity

Norepinephrine is an endogenous neurotransmitter distributed throughout the mammalian brain. In higher cortical structures such as the hippocampus, norepinephrine, via beta adrenergic receptor (AR) activation, has been shown to reinforce the cognitive processes of attention and memory. In this study, we investigated the effect of beta1AR activation on hippocampal cornu ammonis 3 (CA3) network activity. AR expression was first determined using immunocytochemistry with antibodies against beta1ARs, which were found to be exceptionally dense in hippocampal CA3 pyramidal neurons. CA3 network activity was then examined in vitro using field potential recordings in rat brain slices. The selective betaAR agonist isoproterenol caused an enhancement of hippocampal CA3 network activity, as measured by an increase in frequency of spontaneous burst discharges recorded in the CA3 region. In the presence of alphaAR blockade, concentration-response curves for isoproterenol, norepinephrine, and epinephrine suggested that a beta1AR was involved in this response, and the rank order of potency was isoproterenol > norepinephrine = epinephrine. Finally, equilibrium dissociation constants (pK(b)) of subtype-selective betaAR antagonists were functionally determined to characterize the AR subtype modulating hippocampal CA3 activity. The selective beta1AR antagonists atenolol and metoprolol blocked isoproterenol-induced enhancement, with apparent K(b) values of 85 +/- 36 and 3.9 +/- 1.7 nM, respectively. In contrast, the selective beta2AR antagonists ICI-118,551 and butoxamine inhibited isoproterenol-mediated enhancement with apparent low affinities (K(b) of 222 +/- 61 and 9268 +/- 512 nM, respectively). Together, this pharmacological profile of subtype-selective betaAR antagonists indicates that in this model, beta1AR activation is responsible for the enhanced hippocampal CA3 network activity initiated by isoproterenol.

Homeostatic synaptic plasticity can explain post-traumatic epileptogenesis in chronically isolated neocortex.

Chronically isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of post-traumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in chronically isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in chronically isolated neocortex. These burst discharges lasted a few hundred ms, propagated at 1-3 cm/s and consisted of large (10-15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of post-traumatic epileptogenesis.

Spinal and cortical spreading depression enhance spinal cord activity

Cortical spreading depression (CSD) has been suggested to underlie some neurological disorders such as migraine. Despite the intensity with which many investigators have studied SD in the brain, only a few studies have aimed to identify SD in the spinal cord. Here we described the main characteristic features of SD in the spinal cord induced by different methods including various spinal cord injury models and demonstrated that SD enhances the spinal cord activity following a transient suppressive period. These findings suggest that SD may play a role in the mechanisms of spinal neurogenic shock, spinal cord injury, and pain. Furthermore, we studied the effect of CSD on the neuronal activity of the spinal cord. CSD was induced via cortical pinprick injury or KCl injection in the somatosensory cortex. CSD did not propagate into the cervical spinal cord. However, intracellular recordings of the neurons in the dorsal horn of C2 segment, ipsilateral to the hemisphere in which CSD was evoked, showed a transient suppression of spontaneous burst discharges, followed by a significant enhancement of the neuronal activity. This indicates a link between a putative cause of the neurological symptoms and the subsequent pain of migraine.

Sharp wave-like activity in the hippocampus in vitro in mice lacking the gap junction protein connexin 36.

Bath application of kainate (100-300 nM) induced a persistent gamma-frequency (30-80 Hz) oscillation that could be recorded in stratum radiatum of the CA3 region in vitro. We have previously described that in knockout mice lacking the gap junction protein connexin 36 (Cx36KO), gamma-frequency oscillations are reduced but still present. We now demonstrate that in the Cx36KO mice, but not in wild-type (WT), large population field excitatory postsynaptic potentials, or sharp wave-burst discharges, also occurred during the on-going gamma-frequency oscillation. These spontaneous burst discharges were not seen in WT mice. Burst discharges in the Cx36KO mice occurred with a mean frequency of 0.23 +/- 0.11 Hz and were accompanied by a series of fast (approximately 60-115 Hz) population spikes or "ripple" oscillations in many recordings. Intracellular recordings from CA3 pyramidal cells showed that the burst discharges consisted of a depolarizing response and presumed coupling potentials (spikelets) could occasionally be seen either before or during the burst discharge. The burst discharges occurring in Cx36KO mice were sensitive to gap junctions blockers as they were fully abolished by carbenoxolone (200 microM). In control mice we made several attempts to replicate this pattern of sharp wave activity/ripples occurring with the on-going kainate-evoked gamma-frequency oscillation by manipulating synaptic and electrical signaling. Partial disruption of inhibition, in control slices, by bath application of the gamma-aminobutyric acid-A (GABA(A)) receptor antagonist bicuculline (1-4 microM) completely abolished all gamma-frequency activity before any burst discharges occurred. Increasing the number of open gap junctions in control slices by using trimethylamine (TMA; 2-10 mM), in conjunction with kainate, failed to elicit any sharp wave bursts or fast ripples. However, bath application of the potassium channel blocker 4-aminopyridine (4-AP; 20-80 microM) produced a pattern of activity in control mice (13/16 slices), consisting of burst discharges occurring in conjunction with kainate-evoked gamma-frequency oscillations, that was similar to that seen in Cx36KO mice. In a few cases (n = 9) the burst discharges were accompanied by fast ripple oscillations. Carbenoxolone also fully blocked the 4-AP-evoked burst discharges (n = 5). Our results show that disruption of electrical signaling in the interneuronal network can, in the presence of kainate, lead to the spontaneous generation of sharp wave/ripple activity similar to that observed in vivo. This suggests a complex role for electrically coupled interneurons in the generation of hippocampal network activity.

Suppression of epileptiform activity by GABA B receptors in wild type and weaver hippocampus ‘in vitro’

Inhibition by GABA B receptors comprises activation of K + conductance and inhibition of Ca 2+ conductance, thereby reducing action potential dependent transmitter release and silencing neuronal activity. We compared epileptiform activity and its inhibition by the activation of GABA B receptors in homozygous weaver ( wv/wv) and wild type (+/+) CA3 neurons disinhibited by GABA A receptor blockade. In wv/wv mice GABA B receptors have lost their ability to activate K + conductance (J. Neurosci. 18 (1998) 4001). Spontaneous synchronous burst discharges in elevated [K +] o displayed only subtle differences in +/+ and wv/wv slices, except that the GABA B receptor agonist R-baclofen in low concentration (0.1 μM) strongly reduced the frequency of synchronous bursts in +/+ CA3 neurons, but not in wv/wv CA3 neurons. A high affinity GABA B antagonist, CGP55845A (0.5 μM) promoted the incidence of bursts in low [K +] o. Concentration dependence of the reduction of evoked EPSCs was identical in wv/wv and +/+ neurons (IC 50=0.3 μM). Amplitudes of evoked IPSCs were reduced by 0.01 μM R-baclofen in +/+, but not in wv/wv CA3 neurons. The effect of the low concentration was abolished by Ba 2+, which is known to block Kir conductance. The data suggest that activation of Kir conductance is important for the control of GABA release by GABA B autoreceptors in the CA3 network. We conclude that the loss of a contribution of Kir conductance to GABA B receptor-mediated autoinhibition reduces the inclination towards spontaneous bursts of wv/wv CA3 pyramidal neurons.

Impaired inhibition of epileptiform activity by baclofen, but not by adenosine in the weaver hippocampus

The weaver defect results in a loss of baclofen- and adenosine-gated K + conductance in the hippocampus of adult homozygous ( wv/ wv) mice. In addition, suppression of hippocampal epileptiform activity by baclofen is impaired (Jarolimek, W., Bäurle, J., Misgeld, U., 1998. Pore mutation in a G protein-gated inwardly rectifying K + channel subunit causes loss of K + dependent inhibition in weaver hippocampus. Journal of Neuroscience 18, 4001–4007). We used wv/ wv and wild-type (+/+) mice to determine whether K + conductance increases are essential for the suppression of epileptiform activity by R-baclofen and adenosine in disinhibited hippocampal slices. In wv/ wv mice R-baclofen was less potent by two orders of magnitude in reducing the frequency of spontaneous synchronous burst discharges than in +/+ mice. Endogenous adenosine and adenosine A1 receptor agonists differed only slightly in their efficacy to inhibit spontaneous synchronous burst discharges in wv/ wv and +/+ mice. The findings on adenosine A1 receptors suggest that the varied efficacy of R-baclofen in wv/ wv and +/+ mice may not be explained solely on the basis of a loss of ligand-gated K + conductance. Therefore, we investigated the affinity of GABA B receptors for the antagonist CGP55845A in wv/ wv and +/+ hippocampi. Schild plot analysis revealed a K D for the GABA B antagonist CGP55845A 10 fold higher in wv/ wv than in +/+ mice. The data suggest that an alteration of GABA B receptors could contribute to the reduced efficacy of R-baclofen to suppress hippocampal epileptiform activity in weaver mice, while the suppression by adenosine remains largely unaffected.

Roles of calcium- and voltage-sensitive potassium currents in the generation of neuromagnetic signals and field potentials in a CA3 longitudinal slice of the guinea-pig

Objectives: Roles of calcium- and voltage-sensitive potassium currents in generation of neuromagnetic signals and field potentials were evaluated using the longitudinal CA3 slice preparation of the guinea-pig.Methods: Their roles were evaluated by using selective channel blockers (tetraethyl-ammonium (TEA) and 4-aminopyridine (4AP)) and measuring their effects on the two types of signals and intracellular potentials. Fast γ-aminobutyric acid type A inhibition was blocked with picrotoxin.Results: Stimulation of the apical dendrites with an array of extracellular bipolar electrodes produced triphasic evoked magnetic fields with a spike and a slow wave typical of the slices. The evoked potentials in the apical and basal areas of the pyramidal cells closely resembled the magnetic field waveforms. Blockade of the potassium currents with TEA and 4AP had only subtle effects on the initial spike, but dramatically altered the slow wave. They also induced long-lasting spontaneous burst discharges synchronized across the slice. The results could be interpreted in terms of their known pre- and postsynaptic effects. Their post-synaptic effects were confirmed with intracellular recordings.Conclusion: Our results are consistent with a hypothesis that the calcium- and voltage-sensitive potassium currents, especially the A and C currents, play important roles in shaping the slow wave of the neuromagnetic and field potential signals produced by the mammalian hippocampus.

Modulation of burst frequency, duration, and amplitude in the zero-Ca(2+) model of epileptiform activity.

Incubation of hippocampal slices in zero-Ca(2+) medium blocks synaptic transmission and results in spontaneous burst discharges. This seizure-like activity is characterized by negative shifts (bursts) in the extracellular field potential and a K(+) wave that propagates across the hippocampus. To isolate factors related to seizure initiation, propagation, and termination, a number of pharmacological agents were tested. K(+) influx and efflux mechanisms where blocked with cesium, barium, tetraethylammonium (TEA), and 4-aminopyridine (4-AP). The effect of the gap junction blockers, heptanol and octanol, on zero-Ca(2+) bursting was evaluated. Neuronal excitability was modulated with tetrodotoxin (TTX), charge screening, and applied electric fields. Glial cell function was examined with a metabolism antagonist (fluroacetate). Neuronal hyperpolarization by cation screening or applied fields decreased burst frequency but did not affect burst amplitude or duration. Heptanol attenuated burst amplitude and duration at low concentration (0.2 mM), and blocked bursting at higher concentration (0.5 mM). CsCl(2) (1 mM) had no effect, whereas high concentrations (1 mM) of BaCl(2) blocked bursting. TEA (25 mM) and low concentration of BaCl(2) (300 microM) resulted in a two- to sixfold increase in burst duration. Fluroacetate also blocked burst activity but only during prolonged application (>3 h). Our results demonstrate that burst frequency, amplitude, and duration can be independently modulated and suggest that neuronal excitability plays a central role in burst initiation, whereas potassium dynamics establish burst amplitude and duration.

Excitability changes in freeze-induced neocortical microgyria.

A freezing probe was placed on the skull of postnatal day (PN) 1 rats to induce formation of a cerebrocortical microsulcus. Experimental studies were performed on PN days 21-24. At that time point, Nissl-stained sections revealed the presence of a microsulcus similar to that described in human dysplastic cortex. Immunocytochemical staining for parvalbumin, calretinin and calbindin indicated a significant decrease in the number of immunoreactive neurons within the microsulcus and non-significant decreases in regions adjacent to the microsulcus. Staining for the glial markers GFAP and vimentin was increased near the microsulcus. Using in vitro brain slices, recordings were made in cortex adjacent to the microsulcus. Epileptiform activity was observed in response to electrical stimulation near the microsulcus. Analysis of the voltage dependence of evoked epileptiform discharges suggested the presence of an inhibitory component. As previously observed in non-lesioned animals, bath application of 4-aminopyridine induced bicuculline-sensitive spontaneous burst discharges in the presence of excitatory amino acid antagonists. These results suggest that cortical freeze lesions associated with abnormal neuronal migration produce a chronic hyperexcitable state. The findings are consistent with a mechanism involving an alteration, not loss, of inhibition in this model.

Electrical activity in dorsal horns of the spinal cord and in sensorimotor cortex in rats with the spinal pain syndrome

In rats with the spinal pain syndrome caused by penicillin application to the dorsal surface of lumbar segments of the spinal cord, the following changes in evoked potentials were observed in the dorsal horn in L5 segment at the side of penicillin application: a marked increase in primary response and disappearance of the secondary hyperpolarization wave with its replaument by a high-amplitude and long depolarizing wave. In addition to these changes, repetitive spontaneous burst discharges were recorded in the corresponding region of the sensorimotor cortex. Thus, the pathogenic basis of the pain syndrome is a pathological algetic system formed of altered structures that belong to nociceptive apparatus in dorsal horn and higher subdivision of the pain sensory system.

Tetanus toxin-induced seizures in infant rats and their effects on hippocampal excitability in adulthood

A new experimental model of developmental epilepsy is reported. Behavioral and EEG features of seizures produced by unilateral intrahippocampal injection of tetanus toxin in postnatal day 9–11 rats, are described. Within 24–72 h of tetanus toxin injection, rat pups developed frequent and often prolonged seizures which included combinations of repetitive wet dog shakes, and wild running-jumping seizures. Intrahippocampal and cortical surface EEG recordings showed that coincident with these behaviors, electrographic seizures occurred not only in the injected hippocampus, but also in the contralateral hippocampus and bilaterally in the neocortex. Analysis of the interictal EEG revealed multiple independent spike foci. One week following tetanus toxin injection, the number of seizures markedly decreased; however, interictal spiking persisted. After injection rats were allowed to mature some were observed to have unprovoked behavioral seizures and/or epileptiform EEG activity. Mature animals were also studied using in vitro slice techniques. Recordings from hippocampal slices demonstrated spontaneous epileptiform burst discharges in the majority of rats which had tetanus toxin induced seizures as infants. These events occurred in area CA3 and consisted of interictal spikes and intracellularly recorded paroxysmal depolarization shifts (PDSs). On rarer occasions, electrographic seizures were recorded. The use of the tetanus toxin model in developing rats may facilitate a better understanding of the unique features of epileptogenesis in the developing brain and the consequences early-life seizures have on brain maturation and the genesis of epileptic conditions in later life.

Synchronous bursting in a subset of interneurons inhibitory to the goldfish Mauthner cell: synaptic mediation and plasticity.

1. Presynaptic activity in the inhibitory network impinging on the Mauthner (M-) cell was investigated in the goldfish medulla in vivo using extra- and intracellular recordings. The inhibitory presynaptic volley elicited by stimulation of the contralateral vestibular nerve consisted of multiple successive peaks at high frequency (up to 1,000 Hz). Less pronounced multicomponent responses were recorded after antidromic activation of the M-cell. Such high-frequency "oscillatory" field potentials also occurred spontaneously. 2. In intracellular recordings, a subset of inhibitory interneurons showed evoked and spontaneous burst discharge. Burst action potentials were correlated with the peaks in the extracellular volley, suggesting that repetitive firing of these cells is synchronized. Nonbursting cells, on the other hand, fired single action potentials in response to vestibular stimuli and were not activated via the M-cell collateral network. 3. Bursting cells were determined morphologically to be part of the feedback inhibitory circuit. Their responses to stimulation of the contralateral vestibular nerve thus suggest the existence of a crossed excitatory pathway to these interneurons. 4. Vestibular-evoked excitatory postsynaptic potentials (EPSPs) in bursting interneurons had a short latency of 0.781 +/- 0.08 ms (mean +/- SD, n = 18) but reached threshold at 2.25 +/- 1 ms (n = 21). These characteristics are suggestive of a chemically mediated EPSP. Indeed, the evoked synchronous repetitive activity of these cells was prevented by superfusion with excitatory amino-acid receptor antagonists. 5. Bursting neurons showed several characteristics that differentiate them from nonbursting cells, including brief action potentials, plateau responses, and intense spontaneous subthreshold activity. 6. With extracellular recordings, tetanization of contralateral vestibular primary afferents evoked a long-lasting potentiation of oscillatory population responses in 11 of 27 cases. Furthermore in three experiments, the frequency of occurrence of spontaneous bursts was enhanced and a similar facilitation was detected at the intracellular level. 7. We conclude that a subset of interneurons in this inhibitory network is capable of repetitive discharges and that evoked as well as spontaneous firing in this population is synchronized. Although electrical coupling between interneurons may mediate synchronization and intrinsic membrane properties may promote burst activity, our data suggest strongly that repetitive firing requires chemically mediated transmission. Furthermore they indicate that the mechanisms underlying evoked as well as spontaneous bursting in this population show activity-dependent plasticity.