Unbalanced Peptidergic Inhibition in Superficial Neocortex Underlies Spike and Wave Seizure Activity.

Slow spike and wave discharges (0.5-4 Hz) are a feature of many epilepsies. They are linked to pathology of the thalamocortical axis and a thalamic mechanism has been elegantly described. Here we present evidence for a separate generator in local circuits of associational areas of neocortex manifest from a background, sleep-associated delta rhythm in rat. Loss of tonic neuromodulatory excitation, mediated by nicotinic acetylcholine or serotonin (5HT3A) receptors, of 5HT3-immunopositive interneurons caused an increase in amplitude and slowing of the delta rhythm until each period became the "wave" component of the spike and wave discharge. As with the normal delta rhythm, the wave of a spike and wave discharge originated in cortical layer 5. In contrast, the "spike" component of the spike and wave discharge originated from a relative failure of fast inhibition in layers 2/3-switching pyramidal cell action potential outputs from single, sparse spiking during delta rhythms to brief, intense burst spiking, phase-locked to the field spike. The mechanisms underlying this loss of superficial layer fast inhibition, and a concomitant increase in slow inhibition, appeared to be precipitated by a loss of neuropeptide Y (NPY)-mediated local circuit inhibition and a subsequent increase in vasoactive intestinal peptide (VIP)-mediated disinhibition. Blockade of NPY Y1 receptors was sufficient to generate spike and wave discharges, whereas blockade of VIP receptors almost completely abolished this form of epileptiform activity. These data suggest that aberrant, activity-dependent neuropeptide corelease can have catastrophic effects on neocortical dynamics.

Cellular mechanism of neuronal synchronization in epilepsy.

Interictal spikes are a simple kind of epileptic neuronal activity. Field potentials and intracellular recordings observed during interictal spikes of penicillin-treated slices of the hippocampus were reproduced by a mathematical model of a network of 100 hippocampal neurons from the region including CA2 and CA3. The model shows that this form of neuronal synchronization arises because of mutual excitation between neurons, each of which is capable of intrinsic bursting in response to a brief input.

Model of the origin of rhythmic population oscillations in the hippocampal slice.

One goal of mammalian neurobiology is to understand the generation of neuronal activity in large networks. Conceptual schemes have been based on either the properties of single cells or of individual synapses. For instance, the intrinsic oscillatory properties of individual thalamic neurons are thought to underlie thalamic spindle rhythms. This issue has been pursued with a computer model of the CA3 region of the hippocampus that is based on known cellular and synaptic properties. Over a wide range of parameters, this model generates a rhythmic activity at a frequency faster than the firing of individual cells. During each rhythmic event, a few cells fire while most other cells receive synchronous synaptic inputs. This activity resembles the hippocampal theta rhythm as well as synchronized synaptic events observed in vitro. The amplitude and frequency of this emergent rhythmic activity depend on intrinsic cellular properties and the connectivity and strength of both excitatory and inhibitory synapses.

Detecting seizure origin using basic, multiscale population dynamic measures: preliminary findings.

Many types of electrographic seizures are readily identifiable by direct visual examination of electroencephalographic or electrocorticographic recordings. This process can, however, be painstakingly slow, and much effort has been expended to automate the process using various dynamic properties of epileptiform waveforms. As methods have become more subtle and powerful they have been used for seizure subclassification, seizure prediction, and seizure onset identification and localization. Here we concentrate on the last, with reference to seizures of neocortical origin. We briefly review some of the methods used and introduce preliminary results from a very simple dynamic model based on key electrophysiological properties found in some seizure types: occurrence of very fast oscillations (sometimes called ripples), excess gamma frequency oscillations, electroencephalographic/electrocorticographic flattening, and changes in global synchrony. We show how this multiscale analysis may reveal features unique to seizure onset and speculate on the underlying cellular and network phenomena responsible.

Axo-axonal coupling. a novel mechanism for ultrafast neuronal communication.

We provide physiological, pharmacological, and structural evidence that axons of hippocampal principal cells are electrically coupled, with prepotentials or spikelets forming the physiological substrate of electrical coupling as observed in cell somata. Antidromic activation of neighboring axons induced somatic spikelet potentials in neurons of CA3, CA1, and dentate gyrus areas of rat hippocampal slices. Somatic invasion by these spikelets was dependent on the activation of fast Na(+) channels in the postjunctional neuron. Antidromically elicited spikelets were suppressed by gap junction blockers and low intracellular pH. Paired axo-somatic and somato-dendritic recordings revealed that the coupling potentials appeared in the axon before invading the soma and the dendrite. Using confocal laser scanning microscopy we found that putative axons of principal cells were dye coupled. Our data thus suggest that hippocampal neurons are coupled by axo-axonal junctions, providing a novel mechanism for very fast electrical communication.

Could plasticity of inhibition pattern pattern generators?

A modeling study shows that inhibitory synapse plasticity, guided by simple activity-dependent rules, can lead to appropriate phase relationships within an oscillating network.

Neuronal networks for induced '40 Hz' rhythms.

A fast, coherent EEG rhythm, called a gamma or a '40 Hz' rhythm, has been implicated both in higher brain functions, such as the 'binding' of features that are detected by sensory cortices into perceived objects, and in lower level processes, such as the phase coding of neuronal activity. Computer simulations of several parts of the brain suggest that gamma rhythms can be generated by pools of excitatory neurones, networks of inhibitory neurones, or networks of both excitatory and inhibitory neurones. The strongest experimental evidence for rhythm generators has been shown for: (1) neocortical and thalamic neurones that are intrinsic '40 Hz' oscillators, although synchrony still requires network mechanisms; and (2) hippocampal and neocortical networks of mutually inhibitory interneurones that generate collective 40 Hz rhythms when excited tonically.

Gamma-frequency oscillations: a neuronal population phenomenon, regulated by synaptic and intrinsic cellular processes, and inducing synaptic plasticity.

Neurons are extraordinarily complicated devices, in which physical and chemical processes are intercoupled, in spatially non-uniform manner, over distances of millimeters or more, and over time scales of < 1 msec up to the lifetime of the animal. The fact that neuronal populations generating most brain activities of interest are very large-perhaps many millions of cells-makes the task of analysis seem hopeless. Yet, during at least some population activities, neuronal networks oscillate synchronously. The emergence of such oscillations generates precise temporal relationship between neuronal inputs and outputs, thus rendering tractable the analysis of network function at a cellular level. We illustrate this idea with a review of recent data and a network model of synchronized gamma frequency (> 20 Hz) oscillations in vitro, and discuss how these and other oscillations may relate to recent data on back-propagating, action potentials, dendritic Ca2+ transients, long-term potentiation and GABAA receptor-mediated synaptic potentials.

A model of high-frequency ripples in the hippocampus based on synaptic coupling plus axon-axon gap junctions between pyramidal neurons.

So-called 200 Hz ripples occur as transient EEG oscillations superimposed on physiological sharp waves in a number of limbic regions of the rat, either awake or anesthetized. In CA1, ripples have maximum amplitude in stratum pyramidale. Many pyramidal cells fail to fire during a ripple, or fire infrequently, superimposed on the sharp wave-associated depolarization, whereas interneurons can fire at high frequencies, possibly as fast as the ripple itself. Recently, we have predicted that networks of pyramidal cells, interconnected by axon-axon gap junctions and without interconnecting chemical synapses, can generate coherent population oscillations at >100 Hz. Here, we show that such networks, to which interneurons have been added along with chemical synaptic interactions between respective cell types, can generate population ripples superimposed on afferent input-induced intracellular depolarizations. During simulated ripples, interneurons fire at high rates, whereas pyramidal cells fire at lower rates. The model oscillation is generated by the electrically coupled pyramidal cell axons, which then phasically excite interneurons at ripple frequency. The oscillation occurs transiently because rippling can express itself only when axons and cells are sufficiently depolarized. Our model predicts the occurrence of spikelets (fast prepotentials) in some pyramidal cells during sharp waves.

Self-organized synaptic plasticity contributes to the shaping of gamma and beta oscillations in vitro.

gamma (30-70 Hz) followed by beta (10-30 Hz) oscillations are evoked in humans by sensory stimuli and may be involved in working memory. Phenomenologically similar gamma-->beta oscillations can be evoked in hippocampal slices by strong two-site tetanic stimulation. Weaker stimulation leads only to two-site synchronized gamma. In vitro oscillations have memory-like features: (1) EPSPs increase during gamma-->beta; (2) after a strong one-site stimulus, two-site stimulation produces desynchronized gamma; and (3) a single synchronized gamma-->beta epoch allows a subsequent weak stimulus to induce synchronized gamma-->beta. Features 2 and 3 last >50 min and so are unlikely to be caused by presynaptic effects. A previous model replicated the gamma-->beta transition when it was assumed that K(+) conductance(s) increases and there is an ad hoc increase in pyramidal EPSCs. Here, we have refined the model, so that both pyramidal-->pyramidal and pyramidal-->interneuron synapses are modifiable. This model, in a self-organized way, replicates the gamma-->beta transition, along with features 1 and 2 above. Feature 3 is replicated if learning rates, or the time course of K(+) current block, are graded with stimulus intensity. Synaptic plasticity allows simulated oscillations to synchronize between sites separated by axon conduction delays over 10 msec. Our data suggest that one function of gamma oscillations is to permit synaptic plasticity, which is then expressed in the form of beta oscillations. We propose that the period of gamma oscillations, approximately 25 msec, is "designed" to match the time course of [Ca(2+)](i) fluctuations in dendrites, thus facilitating learning.

Differential expression of synaptic and nonsynaptic mechanisms underlying stimulus-induced gamma oscillations in vitro.

Gamma frequency oscillations occur in hippocampus in vitro after brief tetani delivered to afferent pathways. Previous reports have characterized these oscillations as either (1) trains of GABA(A) inhibitory synaptic events mediated by depolarization of both pyramidal cells and interneurons at least in part mediated by metabotropic glutamate and acetylcholine receptors, or (2) field potential oscillations occurring in the near absence of an inhibitory synaptic oscillation when cells are driven by depolarizing GABA responses and local synchrony is produced by field effects. The aim of this study was to investigate factors involved in the differential expression of these synaptically and nonsynaptically gated oscillations. Field effects were undetectable in control recordings but manifested when slices were perfused with hypo-osmotic solutions or a reduced level of normal perfusate. These manipulations also reduced the amplitude of the train of inhibitory synaptic events associated with an oscillation and enhanced the depolarizing GABA component underlying the post-tetanic depolarization. The resulting field oscillation was still dependent, at least in part, on inhibitory synaptic transmission, but spatiotemporal aspects of the oscillation were severely disrupted. These changes were also accompanied by an increase in estimated [K(+)](o) compared with control. We suggest that nonsynaptic oscillations occur under conditions also associated with epileptiform activity and constitute a phenomenon that is distinct from synaptically gated oscillations. The latter remain a viable model for in vivo oscillations of cognitive relevance.

Gap junctions between interneuron dendrites can enhance synchrony of gamma oscillations in distributed networks.

Gamma-frequency (30-70 Hz) oscillations in populations of interneurons may be of functional relevance in the brain by virtue of their ability to induce synchronous firing in principal neurons. Such a role would require that neurons, 1 mm or more apart, be able to synchronize their activity, despite the presence of axonal conduction delays and of the limited axonal spread of many interneurons. We showed previously that interneuron doublet firing can help to synchronize gamma oscillations, provided that sufficiently many pyramidal neurons are active; we also suggested that gap junctions, between the axons of principal neurons, could contribute to the long-range synchrony of gamma oscillations induced in the hippocampus by carbachol in vitro. Here we consider interneuron network gamma: that is, gamma oscillations in pharmacologically isolated networks of tonically excited interneurons, with frequency gated by mutual GABA(A) receptor-mediated IPSPs. We provide simulation and electrophysiological evidence that interneuronal gap junctions (presumably dendritic) can enhance the synchrony of such gamma oscillations, in spatially extended interneuron networks. There appears to be a sharp threshold conductance, below which the interneuron dendritic gap junctions do not exert a synchronizing role.

Neuronal fast oscillations as a target site for psychoactive drugs.

Neuronal oscillations within the electroencephalogram beta and gamma bands (15-80 Hz) are associated with intense mental activity and cognitive function in general. Specifically, recent advances have implicated gamma oscillations in the processing of sensory stimuli and demonstrated that synchronous gamma oscillations, appearing concurrently in spatially separate brain regions, can induce beta activity. beta activity generated in this manner represents established synchronous communication between brain regions and is thought to represent a neuronal network correlate of the "binding phenomenon" in cognitive theory. This review will outline the mechanisms of generation of these oscillations at the cellular and network level, and will highlight the effects of drugs that may modify these mechanisms. Possible modification of fast oscillations by disease processes and clinical intervention are discussed.

Synaptic mechanisms underlying interictal spike initiation in a hippocampal network.

The intrinsic bursting capability of hippocampal neurons is well established. Recent experimental data also imply that CA3 neurons have mutual chemical excitatory interactions. Our previous simulations have shown how these two properties of the hippocampal CA3 region suffice to account for the synchronized burst discharges that occur in the presence of penicillin. Electrotonic interactions via gap junctions have also been described in the CA3 region, but their contribution to synchronization is not clear. We now show that a network of cells connected only by electrotonic junctions does not reproduce the experimental data on synchronization. In combination with chemical synapses, electrotonic junctions can prevent synchronized discharge, increase the degree of synchronization, or prolong the latency from stimulus to discharge. The effect electrotonic junctions have on synchronization of cellular bursting depends intimately on the density and strength of the chemical synapses.

Brain destruction alone does not elevate brain aluminum.

Graphite furnace atomic-absorption spectroscopy was used to measure aluminum concentrations in brain samples from 33 patients dying from a variety of neurologic diseases. Four samples from patients dying of nonneurologic causes also were studied. Nine samples (one from each of nine patients) of Creutzfeldt-Jakob disease brain contained normal amounts of aluminum. Aluminum was increased in 9 of 18 brain specimens with seven different pathologic processes. This included three of seven Alzheimer disease, two of three Huntington disease, two of two Parkinson disease, one of one progressive supranuclear palsy, one of one acoustic neuroma, one of two cerebrovascular disease, and one of two Guamanian amyotrophic lateral sclerosis (ALS). Aluminum was normal in the remaining samples (four normal, two ALS, one multiple sclerosis, one Pick disease, and two Guamanian parkinsonism-dementia). The significance of high aluminum values is not clear, but the normal values from the Creutzfeldt-Jakob cases imply that neuronal destruction per se need not lead to accumulation of aluminum in the brain.

Simulation of intrinsic bursting in CA3 hippocampal neurons.

Dendritic recordings from hippocampal pyramidal cells suggest that bursts of action potentials--riding on a depolarizing wave and terminating in a slow calcium-mediated spike--can be generated locally in the dendrites, as well as at the soma. These data necessitated revision of our earlier model in which bursts at the soma are generated by interaction of two spatially separated conductance systems--a fast-spike sodium mechanism at the soma and a slow-spike calcium mechanism on the apical dendrite. We have introduced into a model of the CA3 hippocampal neuron two experimentally testable concepts: voltage-dependent inactivation of Ik and partial inactivation of ICa by Ca2+ ion. With these mechanisms, the model accurately reproduces bursts generated in either soma or in the apical dendrites by sets of conductances all located in the same respective membrane region. The model is also capable of bursting repetitively in response to continuous stimulation.

Synchronized afterdischarges in the hippocampus: contribution of local synaptic interactions.

In the presence of picrotoxin, spontaneous synchronized bursts followed by afterdischarges were recorded from all pyramidal cell regions of the guinea pig hippocampal slice. Excitatory synaptic potentials, which reversed at approx -5 mV, were found to be associated with both the initial burst and each afterdischarge. Afterdischarges were reversibly blocked, leaving the initial synchronized burst intact, by the application of several excitatory amino acid antagonists or by increasing Mg2+ so that the efficacy of synaptic transmission was reduced. All synchronized activity was suppressed by applying an increased concentration of antagonist or by raising Mg2+ and lowering Ca2+ so that synaptic transmission was completely blocked. This synchronized neuronal activity occurred spontaneously in the CA2-3 region when isolated from the CA1 pyramidal cell area and the dentate gyrus. When CA2 was separated from CA3 a synchronized rhythm of single bursts was observed in CA2, while a different, slower, synchronized population discharge consisting of initial bursts followed by afterdischarges occurred in CA3. The smallest completely isolated segments of the CA3 field which spontaneously generated synchronized afterdischarges, comparable to those observed in the intact slice, measured 500-700 microns along the stratum pyramidable. It is concluded that these afterdischarges depend on local neuronal interactions mediated by chemical synaptic mechanisms which may occur within a single population of as few as 1000 CA3 pyramidal cells. The results are consistent with a repeated activation of the same group of synapses, which may release an excitatory amino acid neurotransmitter, being responsible for the initiation of each afterdischarge.

The initiation and spread of epileptiform bursts in the in vitro hippocampal slice.

We recorded spontaneous synchronized epileptiform bursts from hippocampal slices from guinea pig using an array of 16 extracellular electrodes placed over the stratum pyramidale of CA2 and CA3. The slices were made epileptogenic with the GABA antagonist picrotoxin (or occasionally penicillin). We found that spontaneous bursts always originate at a discrete focus at or near CA2. These bursts spread smoothly and uniformly across CA3 at an average velocity of 0.13 m/s. This velocity is slower than the conduction velocity of the Schaffer collaterals or mossy fibers. Picrotoxin produced afterdischarges following the initial primary burst, and these afterdischarges were found to originate and spread in a fashion nearly identical to the primary burst. These results indicate that CA2 is a unique region which must possess unusual cellular and/or synaptic connectivity properties which result in a decreased threshold for initiation of epileptiform activity. We consider several hypothetical patterns of local synaptic connectivity in the light of these results, and we discuss the possible role of residual inhibition in limiting the spread of synchronized discharges.

Models of the cellular mechanism underlying propagation of epileptiform activity in the CA2-CA3 region of the hippocampal slice.

We have shown experimentally in the previous paper that spontaneous epileptiform activity, as recorded by extracellular field potentials, propagates smoothly across the CA2-CA3 region of the convulsant-treated hippocampal slice of the guinea pig at velocities of about 0.1 m/s. In the present paper, we used computer simulations of either 500 or 1000 cell arrays of model neurons to examine possible mechanisms underlying this propagation. We show that propagation of epileptiform field potentials can be explained plausibly by slow conduction along axons interconnecting CA2-CA3 neurons, provided that there are sufficiently many interconnections. This propagation can take place even if the interconnections occur randomly. The number of interconnections required decreases as the number of synchronously activated cells initiating a population burst increases. Axonal propagation at 0.1 m/s appears to be a plausible assumption, since conduction velocities along Schaffer collaterals have been experimentally estimated to be as slow as 0.2 m/s, and small recurrent collaterals are likely to conduct more slowly than the main axonal branches. If spontaneous synchronized population bursts are initiated by activity in four or fewer cells, then our model requires, for smooth field potential propagation, more interconnections than are believed to occur on the basis of dual intracellular recording.

Synchronized afterdischarges in the hippocampus: simulation studies of the cellular mechanism.

Synchronized multiple bursts represent an epileptic neuronal behavior transitional between synchronized single bursts (interictal spikes) and self-sustained seizures. As described in the previous paper, synchronized multiple bursts occur in hippocampal slices treated with picrotoxin. Multiple bursts consist of an initial prolonged depolarizing burst followed by a rhythmical series of afterdischarges. Both the initial burst and the afterdischarges are synaptically elicited. Our previously described model of the interictal spike illustrates that the generation of a single synchronized burst requires a neuronal network possessing the following properties: intrinsic bursting capability of individual neurons, the presence of recurrent excitatory connections between principal neurons and the blockade of synaptic inhibition. The model demonstrates that the generation of single synchronized bursts involves the initial excitation of one or more neurons, and the subsequent sequential spread of excitation through a population of neurons via recurrent excitatory synapses. In the present study, we examined whether this same mechanism assumed in the previous model could also allow for the generation of synchronized afterdischarges in a population of neurons. We tested the effects of manipulating three network factors: synaptic strength, synaptic density and the refractoriness in the population members following a period of excitation. We discovered that the refractory period following prolonged excitation assumed in our previous model was insufficient to allow for afterdischarge generation. Once sufficient refractoriness was introduced, afterdischarges appeared in our network of neurons. In the present study, the required refractoriness was attributed to the properties of pyramidal cell axons. In principle, such refractoriness might be located elsewhere in the network. The possible contribution of axonal properties is emphasized because of the known intermittent conduction in other axons. Our present model also reproduced other experimental data. Thus, if the network was too small or if synaptic strength was too small, then only a single synchronized burst occurred. The basic assumptions of this model are both biologically plausible and experimentally testable.