Search

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), γ-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 γ-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 μM). In control mice we made several attempts to replicate this pattern of sharp wave activity/ripples occurring with the on-going kainate-evoked γ-frequency oscillation by manipulating synaptic and electrical signaling. Partial disruption of inhibition, in control slices, by bath application of the γ-aminobutyric acid-A (GABAA) receptor antagonist bicuculline (1–4 μM) completely abolished all γ-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 μM) produced a pattern of activity in control mice (13/16 slices), consisting of burst discharges occurring in conjunction with kainate-evoked γ-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.

Electrical coupling between pyramidal cell axons, and between interneuron dendrites, have both been described in the hippocampus. What are the functional roles of the two types of coupling? Interneuron gap junctions enhance synchrony of gamma oscillations (25-70 Hz) in isolated interneuron networks and also in networks containing both interneurons and principal cells, as shown in mice with a knockout of the neuronal (primarily interneuronal) connexin36. We have recently shown that pharmacological gap junction blockade abolishes kainate-induced gamma oscillations in connexin36 knockout mice; without such gap junction blockade, gamma oscillations do occur in the knockout mice, albeit at reduced power compared with wild-type mice. As interneuronal dendritic electrical coupling is almost absent in the knockout mice, these pharmacological data indicate a role of axonal electrical coupling in generating the gamma oscillations. We construct a network model of an experimental gamma oscillation, known to be regulated by both types of electrical coupling. In our model, axonal electrical coupling is required for the gamma oscillation to occur at all; interneuron dendritic gap junctions exert a modulatory effect.

Brief pressure ejection of solutions containing potassium, caesium or rubidium ions into stratum radiatum of the CA1 or CA3 regions of the hippocampal slice evoked a fast network oscillation. The activity evoked lasted approximately 3-25 s with the predominant frequency component being in the gamma frequency range (30-80 Hz), although beta frequency (15-30 Hz) and ultrafast (80 Hz) components could also be seen. The gamma frequency component of the oscillation remained constant, even when large changes in power occurred, and was synchronous across the CA1 region. Measurements with potassium ion-sensitive electrodes revealed that the network oscillation was accompanied by increases (0.5 to 2.0 mM) in the extracellular potassium concentration [K+]o. Bath application of the N-methyl-D-aspartate (NMDA) receptor antagonists D(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 50 microM) had no significant effect but the alpha-amino-3-hydroxy-5-methyl-4-isooxazolepropionic acid (AMPA)/kainate receptor antagonist 2,3,-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide disodium (NBQX; 20 microM) caused a significant reduction (86.7 +/- 4.5 %) in the power in the gamma frequency range. Residual rhythmic activity, presumably arising in the interneuronal network, was blocked by the GABA(A) receptor antagonist bicuculline. The putative gap junction blocker octanol caused a decrease in the power of the gamma frequency component of 75.5 +/- 5.6 %, while carbenoxolone produced a reduction of only 14 +/- 42 %. These experiments demonstrate that a modest increase in exogenous [K+]o in the hippocampus in vitro is sufficient to evoke a fast network oscillation, which is an emergent property of the synaptically and electrically interconnected neuronal network.

The dentate gyrus is a prominent source of gamma frequency activity in the hippocampal formation in vivo. Here we show that transient epochs of gamma frequency network activity (67 ± 12 Hz) can be generated in the dentate gyrus of rat hippocampal slices, following brief pressure ejections of a high-molarity potassium solution onto the molecular layer. Oscillatory activity remains synchronized over distances >300 μm and is accompanied by a modest rise in [K+]o. Gamma frequency oscillations were abolished by a GABAA receptor antagonist demonstrating their dependence on rhythmic inhibition. However, in many cases, higher frequency oscillations (>80 Hz) remained in the absence of synaptic transmission, thus demonstrating that nonsynaptic factors may underlie fast oscillatory activity.

We hypothesized in 1998 that gap junctions might be located between the axons of principal hippocampal neurons, based on the shape of spikelets (fast prepotentials), occurring during gap junction-mediated very fast (to approximately 200 Hz) network oscillations in vitro. More recent electrophysiological, pharmacological and dye-coupling data indicate that axonal gap junctions exist; so far, they appear to be located about 100 microm from the soma, in CA1 pyramidal neurons. Computer modeling and theory predict that axonal gap junctions can lead to very fast network oscillations under three conditions: a) there are spontaneous axonal action potentials; b) the number of gap junctions in the network is neither too low (not less than to approximately 1.5 per cell on average), nor too high (not more than to approximately 3 per cell on average); c) action potentials can cross from axon to axon via gap junctions. Simulated oscillations resemble biological ones, but condition (c) remains to be demonstrated directly. Axonal network oscillations can, in turn, induce oscillatory activity in larger neuronal networks, by a variety of mechanisms. Axonal networks appear to underlie in vivo ripples (to approximately 200 Hz field potential oscillations superimposed on physiological sharp waves), to drive gamma (30-70 Hz) oscillations that appear in the presence of carbachol, and to initiate certain types of ictal discharge. If axonal gap junctions are important for seizure initiation in humans, there could be practical consequences for antiepileptic therapy: at least one gap junction-blocking compound, carbenoxolone, is already in clinical use (for treatment of ulcer disease), and it crosses the blood-brain barrier.

Although there is a great multiplicity of normal brain electrical activities, one can observe defined, relatively abrupt, transitions between apparently normal rhythms and clearly abnormal, higher amplitude, "epileptic" signals; transitions occur over tens of ms to many seconds. Transitional activity typically consists of low-amplitude very fast oscillations (VFO). Examination of this VFO provides insight into system parameters that differentiate the "normal" from the "epileptic." Remarkably, VFO in vitro is generated by principal neuron gap junctions, and occurs readily when chemical synapses are suppressed, tissue pH is elevated, and [Ca(2+)]o is low. Because VFO originates in principal cell axons that fire at high frequencies, excitatory synapses may experience short-term plasticity. If the latter takes the form of potentiation of recurrent synapses on principal cells, and depression of these on inhibitory interneurons, then the stage is set for synchronized bursting - if [Ca(2+)]o recovers sufficiently. Our hypothesis can be tested (in part) in patients, once it is possible to measure brain tissue parameters (pH, [Ca(2+)]o) simultaneously with ECoG.

Although there is a great multiplicity of normal brain electrical activities, one can observe defined, relatively abrupt, transitions between apparently normal rhythms and clearly abnormal, higher amplitude, “epileptic” signals; transitions occur over tens of ms to many seconds. Transitional activity typically consists of low-amplitude very fast oscillations (VFO). Examination of this VFO provides insight into system parameters that differentiate the “normal” from the “epileptic.” Remarkably, VFO in vitro is generated by principal neuron gap junctions, and occurs readily when chemical synapses are suppressed, tissue pH is elevated, and [Ca2+]o is low. Because VFO originates in principal cell axons that fire at high frequencies, excitatory synapses may experience short-term plasticity. If the latter takes the form of potentiation of recurrent synapses on principal cells, and depression of these on inhibitory interneurons, then the stage is set for synchronized bursting – if [Ca2+]o recovers sufficiently. Our hypothesis can be tested (in part) in patients, once it is possible to measure brain tissue parameters (pH, [Ca2+]o) simultaneously with ECoG.

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.

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.

Carbachol (> 20 microM) and kainate (100 nM) induce, in the in vitro CA3 region, synchronized neuronal population oscillations at approximately 40 Hz having distinctive features: (i) the oscillations persist for hours; (ii) interneurons in kainate fire at 5-20 Hz and their firing is tightly locked to field potential maxima (recorded in s. radiatum); (iii) in contrast, pyramidal cells, in both carbachol and kainate, fire at frequencies as low as 2 Hz, and their firing is less tightly locked to field potentials; (iv) the oscillations require GABAA receptors, AMPA receptors and gap junctions. Using a network of 3072 pyramidal cells and 384 interneurons (each multicompartmental and containing a segment of unmyelinated axon), we employed computer simulations to examine conditions under which network oscillations might occur with the experimentally determined properties. We found that such network oscillations could be generated, robustly, when gap junctions were located between pyramidal cell axons, as suggested to occur based on studies of spontaneous high-frequency (> 100 Hz) network oscillations in the in vitro hippocampus. In the model, pyramidal cell somatic firing was not essential for the oscillations. Critical components of the model are (i) the plexus of pyramidal cell axons, randomly and sparsely interconnected by gap junctions; (ii) glutamate synapses onto interneurons; (iii) synaptic inhibition between interneurons and onto pyramidal cell axons and somata; (iv) a sufficiently high rate of spontaneous action potentials generated in pyramidal cell axons. This model explains the dependence of network oscillations on GABA(A) and AMPA receptors, as well as on gap junctions. Besides the existence of axon-axon gap junctions, the model predicts that many of the pyramidal cell action potentials, during sustained gamma oscillations, are initiated in axons.

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.

1 At the molecular level much progress has been made towards elucidating the mechanisms of action of general and dissociative anaesthetics. However, little is known about how these molecular actions may lead to disruption of cognitive function. 2 A promising physiological correlate of cognitive function is the ability of spatially separate areas of the brain to synchronize firing patterns via mutual inhibitory, gamma-frequency (20–80 Hz) electrical oscillations. Here we examine the effects of five different anaesthetic/hypnotic agents with different primary mechanisms of action on these oscillations in the hippocampus. 3 Gamma oscillations were elicited simultaneously at two sites at either end of area CA1 by tetanic stimulation. Such oscillations are synchronous between these areas even when separated by up to c. 4 mm in control conditions. 4 Agents which act directly on GABAA receptor-mediated inhibition had different effects on synchronous gamma oscillations. Thiopental (10–200 μm) markedly disrupted the oscillation and resulting synchrony whereas the benzodiazepines diazepam and temazepam (0.05–1.0 μM) had little effect. 5 The opiate morphine (10–200 μM) and dissociative agent ketamine (10–100 μM) had a different profile of effects on gamma oscillations. However, as with thiopental, both agents markedly disrupted between site synchrony. These three agents demonstrated this effect at aqueous concentrations relevant to anaesthetic ED50. 6 Using the hippocampus as a model neuronal network we propose that, despite differing primary mechanisms of action, anaesthetics may disrupt cognitive function by interfering with the mechanism of generation of synchronous firing patterns between spatially separate areas of the brain. British Journal of Pharmacology (1998) 125, 483–492; doi:10.1038/sj.bjp.0702113

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 of1 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.

Coherent oscillations, in which ensembles of neurons fire in a repeated and synchronous manner, are thought to be important in higher brain functions. In the hippocampus, these discharges are categorized according to their frequency as theta (4-10Hz), gamma (20-80 Hz) and high-frequency (approximately 200 Hz) discharges, and they occur in relation to different behavioural states. The synaptic bases of theta and gamma rhythms have been extensively studied but the cellular bases for high-frequency oscillations are not understood. Here we report that high-frequency network oscillations are present in rat brain slices in vitro, occurring as a brief series of repetitive population spikes at 150-200 Hz in all hippocampal principal cell layers. Moreover, this synchronous activity is not mediated through the more commonly studied modes of chemical synaptic transmission, but is in fact a result of direct electrotonic coupling of neurons, most likely through gap-junctional connections. Thus high-frequency oscillations synchronize the activity of electrically coupled subsets of principal neurons within the well-documented synaptic network of the hippocampus.

Stanford, Ian M., Roger D. Traub, and John G. R. Jefferys. Limbic gamma rhythms. II. Synaptic and intrinsic mechanisms underlying spike doublets in oscillating subicular neurons. J. Neurophysiol. 80: 162–171, 1998. Gamma oscillations were evoked in the subiculum in rat transverse hippocampal slices by tetanic stimulation (200 ms/100 Hz) of either CA1 or subiculum. Gamma oscillations in the subiculum differed from those in CA1 in containing population spike doublets as well as singlets. The present study addresses the origin of this more complex form of gamma oscillation in the subiculum. Intracellular recordings from subicular neurons revealed that 63% of them fired double action potentials on cycles of the gamma oscillation that generated population spike doublets after tetanic stimulation of either CA1 or subiculum. The remaining cells produced excitatory postsynaptic potentials (EPSPs), and occasional single spikes, on each cycle. Neurons that fired occasional single action potentials during gamma rhythms were “regular spiking” cells. They did not produce burst discharges during depolarizing steps, had minimal membrane potential sags on hyperpolarizing steps, and responded to single afferent volleys with a single action potential on an EPSP followed by a large inhibitory postsynaptic potential complex. Fast spiking cells were observed too infrequently to be studied in detail. Neurons that fired doublets during gamma rhythms were “intrinsic burst” (IB) cells. They generated bursts of action potentials on step membrane depolarizations, had significant membrane potential sags on step hyperpolarizations with an anodal break potential on return to rest, and fired multiple action potentials in response to high-intensity single afferent volleys. IB neurons did not fire action potential doublets during 1-s membrane depolarizations. Double action potentials, however, were evoked in these cells by depolarizing pulses at 40 Hz from hyperpolarized membrane potentials (−100 mV). Computer simulations suggest that the hyperpolarization between the depolarizations was essential for action potential doublets. The results in this and the previous paper suggest the following: either CA1 or subiculum alone can generate gamma oscillations gated by local networks of interneurons, oscillations in CA1 project through pyramidal cell axons to subiculum with a time lag expected from axon conduction delays, and oscillating sequences of EPSPs and intrinsic and/or synaptic hyperpolarizing potentials in IB subicular neurons generate gamma frequency spike doublets, which depend on both the intrinsic properties of these neurons and their temporally patterned synaptic input. This phenomenon could amplify gamma output from CA1 and modify its coupling to gamma oscillations in the wider limbic system.

Colling, Simon B., Ian M. Stanford, Roger D. Traub, and John G. R. Jefferys. Limbic gamma rhythms. I. Phase-locked oscillations in hippocampal CA1 and subiculum. J. Neurophysiol. 80: 155–161, 1998. Gamma oscillations (∼40 Hz) were induced in transverse hippocampal slices by tetanic stimulation of CA1 and/or subiculum. Tetanic stimulation of each site elicited population gamma oscillations in the surrounding tissue +]o to 8.2 ± 1.5 mM (mean ± SE). The location of the peak increase corresponded to the site of local gamma generation. Silent areas of CA1 experienced smaller [K+]o increases, to 4.9 ± 0.7 mM. The subiculum, which generated gamma, remained at the baseline 3.0 mM. Although fluctuations in [K+]o may have an impact on the generation of gamma rhythms, they are not necessary for them. Gamma oscillations had similar frequencies in CA1 and subiculum (40.4 ± 2.9 and 43.9 ± 3.1 Hz, respectively). When present in both, the oscillations typically were phase locked with the subiculum lagging by 5.4 ± 1.8 ms. When both CA1 and subiculum were stimulated the lag decreased by 28%. These delays approximate those expected for the conduction velocity of axons between the two regions, here estimated at 0.52 ± 0.07 m/s. Transmission of gamma oscillations from CA1 to subiculum was blocked by the focal addition of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor antagonist, 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione, to the subiculum. Oscillations induced in CA1 by local tetanic stimulation were blocked by focal application of the γ-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline, to CA1. Focal application of bicuculline to the subiculum blocked gamma due to subicular stimulation but not that due to CA1 stimulation. Bath-applied bicuculline disrupted subicular gamma evoked by subicular stimulation and led to a transient period of epileptiform responses before completely blocking responses. The further addition of the GABAB receptor antagonist, CGP 55845A, reversed this block, restoring the epileptic discharges evoked by tetanic stimulation. This suggests that the subiculum differs from hippocampal CA3 and neocortex, in having a powerful GABAB receptor-dependent mechanism to prevent epileptic discharges. The subiculum generates gamma rhythms both in response to local stimulation and to gamma rhythms evoked in CA1. Subicular gamma differs from that in CA1 in the presence of population spike doublets rather than singlets on many cycles. In both areas, generation of gamma by local stimulation depends on GABAA receptors, suggesting that the subiculum shares the interneuronal network mechanism we proposed for CA1.

Oscillations in neuronal population activity within the gamma frequency band (>25 Hz) have been correlated with cognition: Gamma oscillations could bind together features of a sensory stimulus by generating synchrony between discrete cortical areas [Eckhorn, R., Bauer, R., Jordan, W., Brosch, M., Kruse, W., Munk, M. & Reitboeck, H. J. (1989) Biol. Cybern. 60, 121–130; Singer, W. & Gray, C. M. (1995) Annu. Rev. Neurosci. 18, 555–556]. Herein we demonstrate that morphine and β-endorphin disrupt this long-range synchrony of gamma oscillations while leaving the synchrony of local oscillations relatively intact. The effect is caused by a decrease in type A γ-aminobutyric acid receptor-mediated inhibition of both excitatory pyramidal cells and inhibitory interneurons. The effects of morphine on gamma oscillations were blocked by μ-opioid receptor antagonists but not by antagonists of δ or κ receptors. Morphine also produced burst firing in interneurons, because synaptic excitation from pyramidal cells was no longer balanced by synchronous inhibitory postsynaptic potentials. The loss of synchrony of gamma oscillations induced by morphine may constitute one mechanism involved in producing the cognitive deficits that this drug causes clinically.

1. We used transverse and longitudinal rat hippocampal slices to study the synchronization of gamma frequency (> 20 Hz) oscillations, across distances of up to 4.5 mm. gamma oscillations were evoked in the CA1 region by tetanic stimulation at one or two sites simultaneously, and were associated with population spikes. Tetanic stimuli that were strong enough to induce oscillations were associated with depolarization of both pyramidal cells and interneurones, largely produced by activation of metabotropic glutamate receptors. 2. Computer simulations of gamma oscillations were also performed in a model with pyramidal cells and interneurones, arranged in a chain of five cell groups. This model had suggested previously that interneurone networks alone could generate synchronous gamma oscillations locally, but that pyramidal cell firing, by inducing spike doublets in interneurones, was necessary for the occurrence of highly correlated oscillations with small phase lag (< 2.5 ms), in a distributed network possessing long axon conduction delays. 3. In both experiment and model, pyramidal cell spikes occurred in phase with local population spikes, as did the first spike of the interneurone doublet. 4. The conductance of the interneurone alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated conductance was manipulated in the model, while the relation between oscillations at opposite ends of the chain was examined. When the conductance was large enough for doublet firing to be synaptically induced in interneurones, oscillation phase lags were < 2.25 ms across the chain. As predicted, experimental blockade of AMPA receptors resulted in increased phase lags between two sites oscillating simultaneously, compared with control conditions. 5. Both in model and in experiment, when stimuli to the two ends of the network were slightly different, cross-network synchronization occurred with a shorter phase lag at high frequencies than at lower frequencies. 6. These data suggest that, while interneurone networks alone can generate locally synchronized gamma oscillations, firing of pyramidal cells, and the synaptically induced doublet firing in interneurones, contribute to the stability and tight synchrony of the oscillations in distributed networks.

Networks of hippocampal interneurons, with pyramidal neurons pharmacologically disconnected, can generate gamma-frequency (20 Hz and above) oscillations. Experiments and models have shown how the network frequency depends on excitation of the interneurons, and on the parameters of GABAA-mediated IPSCs between the interneurons (conductance and time course). Here we use network simulations to investigate how pyramidal cells, connected to the interneurons and to each other through AMPA-type and/or NMDA-type glutamate receptors, might modify the interneuron network oscillation. With or without AMPA-receptor mediated excitation of the interneurons, the pyramidal cells and interneurons fired in phase during the gamma oscillation. Synaptic excitation of the interneurons by pyramidal cells caused them to fire spike doublets or short bursts at gamma frequencies, thereby slowing the population rhythm. Rhythmic synchronized IPSPs allowed the pyramidal cells to encode their mean excitation by their phase of firing relative to the population waves. Recurrent excitation between the pyramidal cells could modify the phase of firing relative to the population waves. Our model suggests that pools of synaptically interconnected inhibitory cells are sufficient to produce gamma frequency rhythms, but the network behavior can be modified by participation of pyramidal cells.

Synchronous neuronal oscillations in the 30-70 Hz range, known as gamma oscillations, occur in the cortex of many species. This synchronization can occur over large distances, and in some cases over multiple cortical areas and in both hemispheres; it has been proposed to underlie the binding of several features into a single perceptual entity. The mechanism by which coherent oscillations are generated remains unclear, because they often show zero or near-zero phase lags over long distances, whereas much greater phase lags would be expected from the slow speed of axonal conduction. We have previously shown that interneuron networks alone can generate gamma oscillations; here we propose a simple model to explain how an interconnected chain of such networks can generate coherent oscillations. The model incorporates known properties of excitatory pyramidal cells and inhibitory interneurons; it predicts that when excitation of interneurons reaches a level sufficient to induce pairs of spikes in rapid succession (spike doublets), the network will generate gamma oscillations that are synchronized on a millisecond time-scale from one end of the chain to the other. We show that in rat hippocampal slices interneurons do indeed fire spike doublets under conditions in which gamma oscillations are synchronized over several millimetres, whereas they fire single spikes under other conditions. Thus, known properties of neurons and local synaptic circuits can account for tightly synchronized oscillations in large neuronal ensembles.

Summary: Purpose: To analyze the cellular and network mechanisms of sustained seizures, we reviewed the literature and present new data on in vitro epileptiform events. We considered single and recurring synchronized population bursts occurring on a time scale from tens of milliseconds to I min. Methods: We used intracellular and field potential recordings, together with computer network simulations, derived from three types of experimental epileptogenesis: γ-aminobutyric-acidA, (GABAA) blockade, low extracellular [Mg2+]0, and 4-aminopyridine (4-AP). Results: In all three models, sustained depolarizing synaptic currents developed, either through N-methyl-D-aspartate (NMDA) receptors, depolarizing GABAA, receptors, or both. Ectopic action potentials (APs), probably originating in axonal structures, occurred in 4-AP and (as shown by other researchers) after tetanic stimulation; ectopic APs, occurring at sufficient frequency. should also depolarize dendrites, by synaptic excitation, enough to trigger bursts. Conclusions: Ictal-like events appear to arise from two basic mechanisms. The first mechanism consists of sustained dendritic depolarization driving a series of dendritic bursts. The second mechanism consists of an increase in axonal and presynaptic terminal excitability driving a series of bursts analogous to interictal spikes.

Partially synchronous 40-Hz oscillations of cortical neurons have been implicated in cognitive function. Specifically, coherence of these oscillations between different parts of the cortex may provide conjunctive properties to solve the 'binding problem': associating features detected by the cortex into unified perceived objects. Here we report an emergent 40-Hz oscillation in networks of inhibitory neurons connected by synapses using GABAA (gamma-aminobutyric acid) receptors in slices of rat hippocampus and neocortex. These network inhibitory postsynaptic potential oscillations occur in response to the activation of metabotropic glutamate receptors. The oscillations can entrain pyramidal cell discharges. The oscillation frequency is determined both by the net excitation of interneurons and by the kinetics of the inhibitory postsynaptic potentials between them. We propose that interneuron network oscillations, in conjunction with intrinsic membrane resonances and long-loop (such as thalamocortical) interactions, contribute to 40-Hz rhythms in vivo.

High-frequency oscillations (HFOs) are an important part of brain activity in health and disease. However, their origins remain obscure and controversial. One possible mechanism depends on the presence of sparsely distributed gap junctions that electrically couple the axons of principal cells. A plexus of electrically coupled axons is modeled as a random network with bidirectional connections between its nodes. Under certain conditions the network can demonstrate one of two types of oscillatory activity. Type I oscillations (100-200 Hz) are predicted to be caused by spontaneously spiking axons in a network with strong (high-conductance) gap junctions. Type II oscillations (200-300 Hz) require no spontaneous spiking and relatively weak (low-conductance) gap junctions, across which spike propagation failures occur. The type II oscillations are reentrant and self-sustained. Here we examine what determines the frequency of type II oscillations. Using simulations we show that the distribution of loop lengths is the key factor for determining frequency in type II network oscillations. We first analyze spike failure between two electrically coupled cells using a model of anatomically reconstructed CA1 pyramidal neuron. Then network oscillations are studied by a cellular automaton model with random network connectivity, in which we control loop statistics. We show that oscillation periods can be predicted from the network's loop statistics. The shortest loop, around which a spike can travel, is the most likely pacemaker candidate.The principle of one loop as a pacemaker is remarkable, because random networks contain a large number of loops juxtaposed and superimposed, and their number rapidly grows with network size. This principle allows us to predict the frequency of oscillations from network connectivity and visa versa. We finally propose that type I oscillations may correspond to ripples, while type II oscillations correspond to so-called fast ripples.

1. We constructed a branching dendritic compartmental model of a CA3 pyramidal neurone, using experimental data from guinea-pig and rat cells obtained in vitro. The goal was to understand interactions between synaptic events impinging on dendritic branches and voltage- and calcium-dependent currents. The model contained sixty-four soma-dendrite (SD) compartments, an axon initial segment (IS), and four axonal compartments. There were six active conductances in the SD membrane, including a sodium conductance (gNa) and a high-threshold calcium conductance (gCa), with kinetic properties similar to those reported in a previous study. 2. The distribution of conductance densities across the IS and SD was adjusted by testing the model response to antidromic stimulation and current pulses or sustained currents injected into the soma or apical dendrites. As before, gNa was concentrated on and near the soma with lower density in the dendrites, while gCa had a higher density in apical dendrites than at the soma. 3. The model predicts that CA3 pyramidal neurones in media blocking synaptic transmission should fire a burst of action potentials following antidromic stimulation. This was confirmed experimentally in hippocampal slices. 4. Both in the model and in guinea-pig neurones, dendritic IPSCs can delay the onset of bursting. If an IPSC begins soon enough after the first fast action potential, the later burst envelope is attenuated. This effect results from suppression of dendritic Ca2+ electrogenesis. 5. The model predicts that an appropriately timed dendritic IPSC (after the first somatic spike but before the dendritic Ca2+ spike) may suppress the transient local [Ca2+] signal, while having a negligible effect on the electrical output of the neurone. This phenomenon has been reported in guinea-pig Purkinje cells. 6. We conclude that active dendritic currents are critical for regulation of the electrical output of CA3 pyramidal neurones. We suggest also that dendritic [Ca2+] signals might be controlled in individual dendrites independently of action potential outputs, an effect of possible importance for synaptic plasticity.

1. Why does lowering extracellular Mg2+ cause synchronous neuronal bursts and after-discharges? To address this question, a computer model of the CA3 region was constructed with 1000 pyramidal neurones and 100 inhibitory neurones. Pyramidal neurones were multicompartmental and contained five ionic conductances, distributed non-uniformly on the membrane. In parallel, experiments were performed on rat hippocampal slices perfused in solutions without added Mg2+. 2. Model neurones were interconnected randomly as follows. Recurrent excitatory connections between pyramidal neurones, and from pyramidal neurones to inhibitory cells, stimulated both alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (rapid, voltage and Mg2+ independent) and NMDA receptors (slow conductance decay, voltage and Mg2+ dependent). A time-dependent 'desensitization' process was included whereby the NMDA-mediated conductance declined after the onset of synchronized firing. Half of the inhibitory neurones activated GABAA receptors on pyramidal cells (perisomatic, rapid), and half activated GABAB receptors (dendritic, slow onset and decay). 3. We examined patterns of synchronous firing in the pyramidal cells as parameters defining model features were manipulated. These parameters included the maximum conductance of individual synapses, [Mg2+]o, excitatory connectivity, and parameters that defined the NMDA 'desensitization' process. Comparisons were made with experiment where possible. 4. GABAA blockade in 1 mM [Mg2+]o induces single bursts and bursts with after-discharges. Synchronized bursts and after-discharges also occurred in the model when NMDA conductances were sufficiently enhanced, even with GABAA inhibition present. Both in simulated and experimental after-discharges in low-Mg2+ solutions, the level of GABAA inhibition was important in determining the number of secondary bursts and the number of somatic spikes per wave. 5. The model of low-Mg(2+)-induced synchrony predicts that each somatic wave is induced by a dendritic Ca2+ spike and that the dendritic spikes are superimposed on a tonic dendritic depolarization generated by the enhanced NMDA conductance. We further predict the recurrent activation of interneurones by NMDA receptors, based both on experiments and simulations in which AMPA receptors are blocked. 6. Many of the mechanisms underlying low-Mg(2+)-induced after-discharges appear to resemble those underlying picrotoxin-induced after-discharges. These mechanisms can operate in low-Mg2+ solutions because of the increase in NMDA conductance in the recurrent excitatory connections.

Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to >100 Hz) is associated with such cognitive tasks and is thought to provide a substrate for temporal coupling of spatially separate regions of the brain. However, such coupling requires close matching of frequencies in co-active areas, and because the nominal gamma band is so spectrally broad, it may not constitute a single underlying process. Here we show that, for inhibition-based gamma rhythmsin vitroin rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex. A persistent, 30–45 Hz, gap-junction-dependent gamma rhythm dominates rhythmic activity in supragranular layers 2/3, whereas a tonic depolarization-dependent, 50–80 Hz, pyramidal/interneuron gamma rhythm is expressed in granular layer 4 with strong glutamatergic excitation. As a consequence, altering the degree of excitation of the auditory cortex causes bifurcation in the gamma frequency spectrum and can effectively switch temporal control of layer 5 from supragranular to granular layers. Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation. The data suggest that different strategies are used by primary auditory cortex to represent weak and strong inputs, with principal cell firing rate becoming increasingly important as excitation strength increases.

Neurons form transiently stable assemblies that may underlie cognitive functions, including memory formation. In most brain regions, coherent activity is organized by network oscillations that involve sparse firing within a well-defined minority of cells. Despite extensive work on the underlying cellular mechanisms, a fundamental question remains unsolved: how are participating neurons distinguished from the majority of nonparticipators? We used physiological and modeling techniques to analyze neuronal activity in mouse hippocampal slices during spontaneously occurring high-frequency network oscillations. Network-entrained action potentials were exclusively observed in a defined subset of pyramidal cells, yielding a strict distinction between participating and nonparticipating neurons. These spikes had unique properties, because they were generated in the axon without prior depolarization of the soma. GABA A receptors had a dual role in pyramidal cell recruitment. First, the sparse occurrence of entrained spikes was accomplished by intense perisomatic inhibition. Second, antidromic spike generation was facilitated by tonic effects of GABA in remote axonal compartments. Ectopic spike generation together with strong somatodendritic inhibition may provide a cellular mechanism for the definition of oscillating assemblies.

Very fast oscillations (VFO) in neocortex are widely observed before epileptic seizures, and there is growing evidence that they are caused by networks of pyramidal neurons connected by gap junctions between their axons. We are motivated by the spatio-temporal waves of activity recorded using electrocorticography (ECoG), and study the speed of activity propagation through a network of neurons axonally coupled by gap junctions. We simulate wave propagation by excitable cellular automata (CA) on random (Erdös-Rényi) networks of special type, with spatially constrained connections. From the cellular automaton model, we derive a mean field theory to predict wave propagation. The governing equation resolved by the Fisher-Kolmogorov PDE fails to describe wave speed. A new (hyperbolic) PDE is suggested, which provides adequate wave speed v() that saturates with network degree , in agreement with intuitive expectations and CA simulations. We further show that the maximum length of connection is a much better predictor of the wave speed than the mean length. When tested in networks with various degree distributions, wave speeds are found to strongly depend on the ratio of network moments / rather than on mean degree , which is explained by general network theory. The wave speeds are strikingly similar in a diverse set of networks, including regular, Poisson, exponential and power law distributions, supporting our theory for various network topologies. Our results suggest practical predictions for networks of electrically coupled neurons, and our mean field method can be readily applied for a wide class of similar problems, such as spread of epidemics through spatial networks.

Acetylcholine is the primary neuromodulator involved in cortical arousal in mammals. Cholinergic modulation is involved in conscious awareness, memory formation and attention – processes that involve intercommunication between different cortical regions. Such communication is achieved in part through temporal structuring of neuronal activity by population rhythms, particularly in the beta and gamma frequency ranges (12 – 80 Hz). Here we demonstrate, using in vitro and in silico models, that spectrally identical patterns of beta2 and gamma rhythms are generated in primary sensory areas and polymodal association areas by fundamentally different local circuit mechanisms: Glutamatergic excitation induced beta2 frequency population rhythms only in layer 5 association cortex whereas cholinergic neuromodulation induced this rhythm only in layer 5 primary sensory cortex. This region-specific sensitivity of local circuits to cholinergic modulation allowed for control of the extent of cortical temporal interactions. Furthermore, the contrasting mechanisms underlying these beta2 rhythms produced a high degree of directionality, favouring an influence of association cortex over primary auditory cortex.

In vitro hippocampal slice preparations generate a variety of neuronal behaviors involving populations of 1000 neurons or more. Understanding population behavior requires information on single neuron electrophysiology, synoptic connectivity and the properties of different kinds of individual synapses. We describe a model that incorporates these diverse types of data. The model can account for several epileptic behaviors and EEG-like waves.

We have used the hippocampal slice preparation to study cell properties, synaptic organization and synchronized population bursts and oscillations. Our methods are those of electrophysiology and computer modelling. The results shed light on the mechanisms of certain epilepsy types and brain waves that occur in the whole animal. In addition, detailed information on cellular organization of the hippocampus is critical for the evaluation of computational brain theories. To illustrate this point, we shall discuss a particular computational theory of the CA3 region of the hippocampus. This theory concerns the way recurrent excitatory synaptic connections in the hippocampus might be used to define distance in a non-topographic map of the environment. If correct, the theory has specific physiological implications.

We sought to characterize spatial and temporal patterns of electrocorticography (ECoG) very fast oscillations (∼80 Hz, VFOs) prior to seizures in human frontotemporal neocortex, and to develop a testable network model of these patterns.ECoG data were recorded with subdural grids from two preoperative patients with seizures of frontal lobe onset in an epilepsy monitoring unit. VFOs were recorded from rat neocortical slices. A "cellular automaton" model of network oscillations was developed, extending ideas of Traub et al. (Neuroscience, 92, 1999, 407) and LewisRinzel (Network: Comput Neural Syst, 11, 2000, 299); this model is based on postulated electrical coupling between pyramidal cell axons.Layer 5 of rat neocortex, in vitro, can generate VFOs when chemical synapses are blocked. Human epileptic neocortex, in situ, produces preseizure VFOs characterized by the sudden appearance of "blobs" of activity that evolve into spreading wavefronts. When wavefronts meet, they coalesce and propagate perpendicularly but never pass through each other. This type of pattern has been described by LewisRinzel in cellular automaton models with spatially localized connectivity, and is demonstrated here with 120,000- to 5,760,000-cell models. We provide a formula for estimating VFO period from structural parameters and estimate the spatial scale of the connectivity.These data provide further evidence, albeit indirect, that preseizure VFOs are generated by networks of pyramidal neurons coupled by gap junctions, each predominantly confined to pairs of neurons having somata separated by∼1-2 mm. Plausible antiepileptic targets are tissue mechanisms, such as pH regulation, that influence gap-junction conductance.

1. We have developed a 19-compartment cable model of a guinea pig CA3 pyramidal neuron. Each compartment is allowed to contain six active ionic conductances: gNa, gCa, gK(DR) (where DR stands for delayed rectifier), gK(A), gK(AHP), and gK(C). THe conductance gCa is of the high-voltage activated type. The model kinetics for the first five of these conductances incorporate voltage-clamp data obtained from isolated hippocampal pyramidal neurons. The kinetics of gK(C) are based on data from bullfrog sympathetic neurons. The time constant for decay of submembrane calcium derives from optical imaging of Ca signals in Purkinje cell dendrites. 2. To construct the model from available voltage-clamp data, we first reproduced current-clamp records from a model isolated neuron (soma plus proximal dendrites). We next assumed that ionic channel kinetics in the dendrites were the same as in the soma. In accord with dendritic recordings and calcium-imaging data, we also assumed that significant gCa occurs in dendrites. We then attached sections of basilar and apical dendritic cable. By trial and error, we found a distribution (not necessarily unique) of ionic conductance densities that was consistent with current-clamp records from the soma and dendrites of whole neurons and from isolated apical dendrites. 3. The resulting model reproduces the Ca(2+)-dependent spike depolarizing afterpotential (DAP) recorded after a stimulus subthreshold for burst elicitation. 4. The model also reproduces the behavior of CA3 pyramidal neurons injected with increasing somatic depolarizing currents: low-frequency (0.3-1.0 Hz) rhythmic bursting for small currents, with burst frequency increasing with current magnitude; then more irregular bursts followed by afterhyperpolarizations (AHPs) interspersed with brief bursts without AHPs; and finally, rhythmic action potentials without bursts. 5. The model predicts the existence of still another firing pattern during tonic depolarizing dendritic stimulation: brief bursts at less than 1 to approximately 12 Hz, a pattern not observed during somatic stimulation. These bursts correspond to rhythmic dendritic calcium spikes. 6. The model CA3 pyramidal neuron can be made to resemble functionally a CA1 pyramidal neuron by increasing gK(DR) and decreasing dendritic gCa and gK(C). Specifically, after these alterations, tonic depolarization of the soma leads to adapting repetitive firing, whereas stimulation of the distal dendrites leads to bursting. 7. A critical set of parameters concerns the regulation of the pool of intracellular [Ca2+] that interacts with membrane channels (gK(C) and gK(AHP)), particularly in the dendrites.(ABSTRACT TRUNCATED AT 400 WORDS)

From the known properties of the hippocampal slice the authors have abstracted a cellular automaton model that incorporates many of the features of the CA3 region of the hippocampus, but which represents the neurons as binary variables. The model is simple enough to allow efficient numerical simulation. Results of simulations of a finite-size model with up to 10000 neurons, as well as the properties of the corresponding infinite-size limit, are shown to be in good agreement with the observed collective behaviour of hippocampal slices.

Very fast oscillations (VFO; > 75 Hz) occur transiently in vivo, in the cerebellum of mice genetically modified to model Angelman syndrome, and in a mouse model of fetal alcohol syndrome. We recently reported VFO in slices of mouse cerebellar cortex (Crus I and II of ansiform and paramedian lobules), either in association with gamma oscillations (approximately 40 Hz, evoked by nicotine) or in isolation [evoked by nicotine in combination with gamma-aminobutyric acid (GABA)(A) receptor blockade]. The experimental data suggest a role for electrical coupling between Purkinje cells (blockade of VFO by drugs reducing gap junction conductance and spikelets in some Purkinje cells); and the data suggest the specific involvement of Purkinje cell axons (because of field oscillation maxima in the granular layer). We show here that a detailed network model (1000 multicompartment Purkinje cells) replicates the experimental data when gap junctions are located on the proximal axons of Purkinje cells, provided sufficient spontaneous firing is present. Unlike other VFO models, most somatic spikelets do not correspond to axonal spikes in the parent axon, but reflect spikes in electrically coupled axons. The model predicts gating of VFO frequency by g(Na) inactivation, and experiments prolonging this inactivation time constant, with beta-pompilidotoxin, are consistent with this prediction. The model also predicts that cerebellar VFO can be explained as an electrically coupled system of axons that are not intrinsic oscillators: the electrically uncoupled cells do not individually oscillate (in the model) and axonal firing rates are much lower in the uncoupled state than in the coupled state.

Cognitive disruption in schizophrenia is associated with altered patterns of spatiotemporal interaction associated with multiple electroencephalogram (EEG) frequency bands in cortex. In particular, changes in the generation of gamma (30-80 Hz) and beta2 (20-29 Hz) rhythms correlate with observed deficits in communication between different cortical areas. Aspects of these changes can be reproduced in animal models, most notably those involving acute or chronic reduction in glutamatergic synaptic communication mediated by N-methyl D-aspartate (NMDA) receptors. In vitro electrophysiological and immunocytochemical approaches afforded by such animal models continue to reveal a great deal about the mechanisms underlying EEG rhythm generation and are beginning to uncover which basic molecular, cellular, and network phenomena may underlie their disruption in schizophrenia. Here we briefly review the evidence for changes in gamma-aminobutyric acidergic (GABAergic) and glutamatergic function and address the problem of region specificity of changes with quantitative comparisons of effects of ketamine on gamma and beta2 rhythms in vitro. We conclude, from available evidence, that many observed changes in markers for GABAergic function in schizophrenia may be secondary to deficits in NMDA receptor-mediated excitatory synaptic activity. Furthermore, the broad range of changes in cortical dynamics seen in schizophrenia -- with contrasting effects seen in different brain regions and for different frequency bands -- may be more directly attributable to underlying deficits in glutamatergic neuronal communication rather than GABAergic inhibition alone.

We describe a transition from bursting to rapid spiking in a reduced mathematical model of a cerebellar Purkinje cell. We perform a slow-fast analysis of the system and find that -- after a saddle node bifurcation of limit cycles -- the full model dynamics follow temporarily a repelling branch of limit cycles. We propose that the system exhibits a dynamical phenomenon new to realistic, biophysical applications: torus canards., Comment: 4 pages; 4 figures (low resolution); updated following peer-review: language and definitions updated, Figures 1 and 4 updated, typos corrected, references added and removed

The seminal in vivo work of Mircea Steriade and his colleagues has, as is always the case with the most insightful and creative scientists, raised many serious questions: questions, for example, of the detailed cellular and molecular mechanisms of the phenomena they discovered. In our tribute to this great investigator, we shall present some examples, based on our in vitro and modeling work, that shed light on some of his remarkable breakthroughs: the slow oscillation of sleep ( 70 Hz) oscillations.

The neocortex generates rhythmic electrical activity over a frequency range covering many decades. Specific cognitive and motor states are associated with oscillations in discrete frequency bands within this range, but it is not known whether interactions and transitions between distinct frequencies are of functional importance. When coexpressed rhythms have frequencies that differ by a factor of two or more interactions can be seen in terms of phase synchronization. Larger frequency differences can result in interactions in the form of nesting of faster frequencies within slower ones by a process of amplitude modulation. It is not known how coexpressed rhythms, whose frequencies differ by less than a factor of two may interact. Here we show that two frequencies (gamma – 40 Hz and beta2 – 25 Hz), coexpressed in superficial and deep cortical laminae with low temporal interaction, can combine to generate a third frequency (beta1 – 15 Hz) showing strong temporal interaction. The process occurs via period concatenation, with basic rhythm-generating microcircuits underlying gamma and beta2 rhythms forming the building blocks of the beta1 rhythm by a process of addition. The mean ratio of adjacent frequency components was a constant – approximately the golden mean – which served to both minimize temporal interactions, and permit multiple transitions, between frequencies. The resulting temporal landscape may provide a framework for multiplexing – parallel information processing on multiple temporal scales.

Publisher Summary This chapter reviews data indicating that, in diverse seizure models, very fast oscillations (VFO, >70 Hz) in neuronal network activity constitute the initial pre-seizure event; and indicating further that VFO is generated, in part, because gap junctions exist between the axons of principal cortical neurons. It illustrates examples and review literature demonstrating that field potential oscillations—at frequencies from ∼20 Hz to >100 Hz—occur prior to the onset of electrographic seizures in humans and experimental animals, and in vitro as well. Following this, it explores the physiological and anatomical background, wherein it discusses the evidence for gap junction-mediated electrical coupling between principal cell axons and it discusses the mechanisms of very fast network oscillations (>70 Hz, VFO) that depend on, or are influenced by, gap junctions between principal cells. It emphasizes that oscillations, occurring at the frequencies observed prior to seizures, cannot be understood without taking into account gap junctions at distinctive cellular locations and the diverse physiological effects such gap junctions can exert. It also presents some examples of VFO occurring in conjunction with epileptiform events. Furthermore, it considers the in vitro model in which epochs of gamma oscillations, lasting seconds, alternate with brief epileptiform bursts lasting hundreds of milliseconds. Finally, it addresses the problem of how very fast oscillations (sometimes lasting >10 s) can occur prior to sustained electrographic seizure activity. The solution to this problem is not yet experimentally available, but enough is known that, using network models, some reasonable possibilities can be presented.

1. Spontaneous discharges that resemble interictal spikes arise in area CA3 b/c of rat hippocampal slices bathed in 8.5 mM [K+]o. Excitatory postsynaptic potentials (EPSPs) also appear at irregular intervals in these cells. The role of local synaptic excitation in burst initiation was examined with intracellular and extracellular recordings from CA3 pyramidal neurons. 2. Most (70%) EPSPs were small (less than 2 mV in amplitude), suggesting that they were the product of quantal release or were evoked by a single presynaptic action potential in another cell. It is unlikely that most EPSPs were evoked by a presynaptic burst of action potentials. Indeed, intrinsic burst firing was not prominent in CA3 b/c pyramidal cells perfused in 8.5 mM [K+]o. 3. The likelihood of occurrence and the amplitude of EPSPs were higher in the 50-ms interval just before the onset of each burst than during a similar interval 250 ms before the burst. This likely reflects increased firing probability of CA3 neurons as they emerge from the afterhyperpolarization (AHP) and conductance shunt associated with the previous burst. 4. Perfusion with 2 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a potent quisqualate receptor antagonist, decreased the frequency of EPSPs in CA3 b/c neurons from 3.6 +/- 0.9 to 0.9 +/- 0.3 (SE) Hz. Likewise, CNQX reversibly reduced the amplitude of evoked EPSPs in CA3 b/c cells. 5. Spontaneous burst firing in 8.5 mM [K+]o was abolished in 11 of 31 slices perfused with 2 microM CNQX.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta2 frequency (20–30 Hz) oscillations appear over somatosensory and motor cortices in vivo during motor preparation and can be coherent with muscle electrical activity. We describe a beta2 frequency oscillation occurring in vitro in networks of layer V pyramidal cells, the cells of origin of the corticospinal tract. This beta2 oscillation depends on gap junctional coupling, but it survives a cut through layer 4 and, hence, does not depend on apical dendritic electrogenesis. It also survives a blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors or a blockade of GABA A receptors that is sufficient to suppress gamma (30–70 Hz) oscillations in superficial cortical layers. The oscillation period is determined by the M type of K + current.

The electrical correlates of clinical seizures, and of experimental models of seizures, are recognized because neurons behave differently than normal. Individual neurons do unusual things, and neuronal activities become correlated with each other in ways that are not observed under physiologic conditions. Single neurons may fire bursts of action potentials superimposed on large depolarizations, and the bursts may recur rhythmically over a wide range of frequencies (1 Hz to 25 Hz); periods of noisy subthreshold activity can occur; and firing can even be suppressed in some neurons. At the population level, nearby neurons tend to fire action potentials, or generate bursts, that are temporally locked together on a few-milliseconds time scale, so that large voltage transients are generated in extracellular fields. Very fast oscillations (80 Hz) in neuronal aggregates may occur before, during, or after such large field potentials. Finally, cellular activities may even be correlated across large brain regions. The authors review some of the means by which cellular intrinsic properties, synaptic interactions, and electrical coupling via gap junctions, all contribute to the anomalous population activities characteristic of seizures. Also reviewed are some of the data suggesting that the requisite gap junctions are located on the axons of glutamatergic neurons.

Very fast oscillations, 80 Hz and greater (designated here VFOs or “ripples”) have been observed in the hippocampus and neocortex, under a variety of conditions that are summarized briefly later. VFOs may be of relevance for normal brain function ( 1 – 4 ) and could also be of relevance in the initiation of focal epileptic seizures ( 5 , 6 ). To determine whether such relevance indeed exists, an understanding of the cellular mechanisms of VFOs is essential. For purposes of this commentary, I shall assume that all forms of VFOs are governed by a few common basic underlying principles. Future experimental data may show that assumption to be false, but for now, the assumption at least allows the formulation of straightforward hypotheses that could stimulate experiments.

High frequency oscillations (> 80–90 Hz) occur in neocortex and hippocampus in vivo where they are associated with specific behavioural states and more classical EEG frequency bands. In the hippocampus in vitro these oscillations can occur in the absence of pyramidal neuronal somatodendritic compartments and are temporally correlated with on-going, persistent gamma frequency oscillations. Their occurrence in the hippocampus is dependent on gap-junctional communication and it has been suggested that these high frequency oscillations originate as collective behaviour in populations of electrically coupled principal cell axonal compartments. Here we demonstrate that the superficial layers of medial entorhinal cortex can also generate high frequency oscillations associated with gamma rhythms. During persistent gamma frequency oscillations high frequency oscillations occur with a high bispectral coherence with the field gamma activity. Bursts of high frequency oscillations are temporally correlated with both the onset of compound excitatory postsynaptic potentials in fast-spiking interneurones and spikelet potentials in both pyramidal and stellate principal neurones. Both the gamma frequency and high frequency oscillations were attenuated by the gap junction blocker carbenoxolone. These data suggest that high frequency oscillations may represent the substrate for phasic drive to interneurones during persistent gamma oscillations in the medial entorhinal cortex.