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J G Jefferys

Publications and source records attributed to J G Jefferys.

At least 19 recordsLinked to original sources
PubMed1997

Recurrent excitatory postsynaptic potentials induced by synchronized fast cortical oscillations.

Gamma frequency (about 20-70 Hz) oscillations occur during novel sensory stimulation, with tight synchrony over distances of at least 7 mm. Synchronization in the visual system has been proposed to reflect coactivation of different parts of the visual field by a single spatially extended object. We have shown that intracortical mechanisms, including spike doublet firing by interneurons, can account for tight long-range synchrony. Here we show that synchronous gamma oscillations in two sites also can cause long-lasting (>1 hr) potentiation of recurrent excitatory synapses. Synchronous oscillations lasting >400 ms in hippocampal area CA1 are associated with an increase in both excitatory postsynaptic potential (EPSP) amplitude and action potential afterhyperpolarization size. The resulting EPSPs stabilize and synchronize a prolonged beta frequency (about 10-25 Hz) oscillation. The changes in EPSP size are not expressed during non-oscillatory behavior but reappear during subsequent gamma-oscillatory events. We propose that oscillation-induced EPSPs serve as a substrate for memory, whose expression either enhances or blocks synchronization of spatially separated sites. This phenomenon thus provides a dynamical mechanism for storage and retrieval of stimulus-specific neuronal assemblies.

Animals↗
PubMed1997

Spatiotemporal patterns of gamma frequency oscillations tetanically induced in the rat hippocampal slice.

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.

Action Potentials↗
PubMed1997

Mossy fibre reorganization in the hippocampus of prion protein null mice.

Mice lacking prion protein (PrP-null) are resistant to transmissible spongiform encephalopathies. However, the normal functions of this highly conserved protein remain controversial. This study examines whether PrP-null mice develop normal neuronal pathways, specifically the mossy fibre pathway, within the hippocampus. Timm stained hippocampal sections from the PrP-null group had more granules than the controls in: the granule cell layer, the inner molecular layer of the dentate gyrus, and the infrapyramidal region of CA3. This resembles the mossy fibre collateral and terminal sprouting seen in certain epilepsies. The abnormal connectivity might be predicted to promote epileptiform activity, but extracellular electrophysiological recordings from the granule cell layer revealed a reduced excitability in the PrP-null group, both with and without blockade of GABA(A) receptor-mediated inhibition. We propose that reorganization of neuronal circuity is a feature of PrP-null mice.

Analysis of Variance↗
PubMed1997

Simulation of gamma rhythms in networks of interneurons and pyramidal cells.

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.

Electroencephalography↗
PubMed1996

Dendritic shrinkage and dye-coupling between rat hippocampal CA1 pyramidal cells in the tetanus toxin model of epilepsy.

A small dose of tetanus toxin injected into the rat hippocampus produces a chronic model of temporal lobe epilepsy. We have examined whether morphological changes occur in hippocampal CA1 pyramidal cells in this model by using intracellular injections of biocytin. Eight weeks after the injection of tetanus toxin, significantly more "dye-coupled' cells were found in this group than in the buffer (control) injected group (63% compared with 7%). Half of these coupled cells appeared to be linked at the soma, and the other half by dendrodendritic contacts. Analysis of the dendritic trees revealed that the tetanus toxin group showed a decrease in complexity around the proximal to mid-apical dendritic regions and around the mid- to distal basal dendritic regions. The dye-coupling indicates that electrotonic interaction is induced or strengthened between hippocampal neurones, possibly as a result of the epilepsy-induced dendritic damage.

Animals↗
PubMed1996

A mechanism for generation of long-range synchronous fast oscillations in the cortex.

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.

Action Potentials↗
PubMed1996

Analysis of gamma rhythms in the rat hippocampus in vitro and in vivo.

1. We have shown previously, with experimental and computer models, how a '40 Hz' (gamma) oscillation can arise in networks of hippocampal interneurones, involving mutual GABAA-mediated synaptic inhibition and a source of tonic excitatory input. Here, we explore implications of this model for some hippocampal network phenomena in the rat in vitro and in vivo. 2. A model network was constructed of 1024 CA3 pyramidal cells and 256 interneurones. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), NMDA (N-methyl-D-aspartate), GABAA and GABAB receptors were simulated on pyramidal cells and on interneurones. 3. In both model and experiment, the frequency of network oscillations, in the gamma range, depended upon three parameters: GABAA conductance and decay time constant in interneurone-->interneurone connections, and the driving current to the interneurones. 4. The model of gamma rhythm predicts an average zero phase lag between firing of pyramidal cells and interneurones, as observed in the rat hippocampus in vivo. The model also reproduces a gamma rhythm whose frequency changes with time, at theta frequency (about 5 Hz). This occurs when there is 5 Hz modulation of a tonic signal to chandelier and basket cells. 5. Synchronized bursts can be produced in the model by several means, including partial blockade of GABAA receptors or of AMPA receptors on interneurones, or by augmenting AMPA-mediated EPSCs. In all of these cases, the burst can be followed by a 'tail' of transiently occurring gamma waves, a phenomenon observed in the hippocampus in vivo following sharp waves. This tail occurs in the model because of delayed excitation of the interneurones by the synchronized burst. A tail of gamma activity was found after synchronized epileptiform bursts both in the hippocampal slice (CA3 region) and in vivo. 6. Our data suggest that gamma-frequency EEG activity arises in the hippocampus when pools of interneurones receive a tonic or slowly varying excitation. The frequency of the oscillation depends upon the strength of this excitation and on the parameters regulating the inhibitory coupling between the interneurones. The interneurone network output is then imposed upon pyramidal neurones in the form of rhythmic synchronized IPSPs.

Action Potentials↗
PubMed1996

Hippocampal slices from prion protein null mice: disrupted Ca(2+)-activated K+ currents.

The intrinsic properties of hippocampal CA1 pyramidal cells were examined in mice lacking prion protein (PrP-null). The resting potentials, time constants, amplitude of the medium afterhyperpolarization (AHP) and spike firing accommodation did not differ from the control group. The PrP-null group differed in having lower input resistances, a lack of the late AHP and of a charybdotoxin-sensitive summated AHP. We propose that CA(2+)-activated K+ currents, in particular IAHP, are disrupted in PrP-null mice.

Action Potentials↗
PubMed1996

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.

Animals↗
PubMed1996

Review of the role of inhibitory neurons in chronic epileptic foci induced by intracerebral tetanus toxin.

Blocking inhibition provides one of the most common experimental means of triggering epileptic activity in hippocampus and neocortex. However, it has proved much more difficult to show that chronic models of epilepsies are due to disinhibition. One problem is knowing how much inhibition needs to be blocked to provide a sufficient mechanism for epileptic activity. We have found that inhibitory (GABAA) transmission, estimated from evoked monosynaptic IPSCs, must be reduced to 17% of their control amplitude (by 4-7 microM bicuculline) before hippocampal slices generate all-or-none epileptic discharges. Similar estimates of inhibition in chronic epileptic foci induced by intrahippocampal injection of tetanus toxin showed that monosynaptic IPSCs dropped to 10% of control in the injected hippocampus during the first 2 weeks after injection. At all other stages of the active epileptic foci in the two hippocampi the reduction in IPSCs was not alone sufficient for epileptic activity; at 4-6 weeks IPSCs were normal despite continued epileptic activity. One likely mechanism for the late epileptic activity is a reduction of either the intrinsic excitability, or the synaptic excitation, of inhibitory interneurons so they fail to be recruited normally. Alternative mechanisms include the formation of new excitatory connections, as found at modest levels in the dentate gyrus. Several mechanisms may play a part in chronic foci such as those induced by tetanus toxin, either acting together, or sequentially during the progression of the epileptic focus.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1996

Effects of intravenous anaesthetic agents on fast inhibitory oscillations in the rat hippocampus in vitro.

1. General anaesthetic agents prevent awareness of sensory input and subsequent recall of sensory events after administration. The mechanisms involved in higher sensory processing, including awareness and recall, are not fully elucidated. However, fast oscillations in neuronal activity in the 20-80 Hz (gamma) range have been strongly implicated. Here we have investigated the effects of two anaesthetic agents and a sedative/hypnotic drug on these oscillations. 2. Trains of fast oscillations, shown previously to be shaped by gamma-aminobutyric acid (GABAA) receptor activation, were evoked by pressure ejection of L-glutamate (10 nM) onto the perisomatic region of hippocampal area CAI in the presence of 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP), 50 microM, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX), 50 microM and 2-hydroxysaclofen, 0.2 mM. 3. Thiopentone (10-200 microM) and propofol (0.5-10 microM) dose-dependently decreased both the maximum oscillation frequency, by approx. 90%, and the incidence of evoked rhythmic oscillations by approx. 60%. Diazepam (0.05-1 microM) decreased maximum oscillation frequency by about 40% but did not affect the incidence of evoked oscillations. 4. The similar effects of thiopentone and propofol were mediated by both a large (about 600%) increase in the decay constant (tau D) of GABAA receptor-mediated inhibitory postsynaptic currents (i.p.s.cs) and a bicuculline-sensitive leak current. The two drugs had differing effects on i.p.s.c. amplitude. Diazepam caused a small increase in tau D (about 170%) and did not alter leak currents at the doses used. 5. Effects of the anaesthetic agents were seen on the above measurements at similar concentrations to those estimated in the CNS during clinical and veterinary anaesthesia. We suggest that the effects on fast oscillations associated with cognition may contribute to the mechanism by which these agents produce general anaesthesia.

Anesthetics↗
PubMed1996

On the structure of ictal events in vitro.

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 1 min. METHODS: We used intracellular and field potential recordings, together with computer network simulations, derived from three types of experimental epileptogenesis: gamma-aminobutyric-acidA (GABAA) blockade, low extracellular [Mg2+]o, 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.

4-Aminopyridine↗
PubMed1995

Cellular mechanisms of 4-aminopyridine-induced synchronized after-discharges in the rat hippocampal slice.

1. We constructed a model of the in vitro rodent CA3 region with 128 pyramidal neurones and twenty-four inhibitory neurones. The model was used to analyse synchronized firing induced in the rat hippocampal slice by 4-aminopyridine (4-AP), a problem simultaneously studied in experiments in rat hippocampal slices. N-methyl-D-aspartate (NMDA) receptors were blocked. 2. Consistent with a known action of 4-AP, unitary EPSCs were assumed to be large and prolonged. With augmented EPSCs, spontaneous synchronized bursts occurred in the model if random ectopic axonal spikes were present. We observed probable antidromic spikes and miniature spikes experimentally. 3. Consistent with experiment, model synchronized bursts were preceded by a period of about 100 ms of increased unit activity and cell depolarization. In the model, this was caused in part by EPSPs consequent to ectopic axonal spikes. 4. After widespread firing had begun, full-blown synchrony in the model required orthodromic EPSPs. A single synchronized burst, once initiated, could proceed without further ectopic activity. 5. A depolarizing change in reversal potential for dendritic GABAA favoured the occurrence of synchronized after-discharges in the model. Consistent with this, bicuculline was found to block after-discharges in slices bathed in 4-AP (70 microM) during NMDA blockade. 6. These data indicate that, even with synaptic inhibition present, ectopic spikes can 'set the stage' for synchronized activity by depolarizing pyramidal cell dendrites, but that recurrent orthodromic EPSPs are required for expression of this synchrony. When synaptic inhibition is present, EPSCs may need to be larger than usual for synchrony to take place. Secondary bursts in 4-AP appear to be driven in part by a depolarizing GABAA-mediated current.

4-Aminopyridine↗
PubMed1995

Erosion of inhibition contributes to the progression of low magnesium bursts in rat hippocampal slices.

1. Bathing slices of rat hippocampus in media containing no magnesium ions results in epileptic discharges that originate in hippocampal area CA3. These discharges increase in severity gradually over periods of hours. 2. The progression of epileptic activity was much slower than the equilibration of extracellular magnesium activity and the resulting increase in strength of monosynaptic NMDA receptor-mediated excitation. Its time course matched that of a progressive decrease in pharmacologically isolated, evoked GABAA receptor-mediated inhibitory postsynaptic current (IPSC) in the CA3 pyramidal cells. Conductance decreased to 37 +/- 6% of control values after 4 h. Responses to exogenous GABA application decreased to 52 +/- 12%. 3. Maximal IPSC conductance in 0 mM extracellular Mg2+ ([Mg2+]o) also decreased gradually when epileptic activity was abolished by bath application of 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 50 microM D-2-amino-5-phosphonovaleric acid (D-APV) throughout the 4 h incubation period. It reached 61 +/- 8% of control values, a significantly smaller decline than that seen after 4 h of epileptic activity. 4. The decrease in mean IPSC conductance only partially reversed when the recording electrode contained 100 mM Mg2+. Complete recovery of IPSC strength occurred when electrodes also contained either 50 mM MgATP or 20 mM BAPTA. Reintroduction of 1 mM [Mg2+]o rapidly abolished epileptic activity and caused a slow, partial increase in IPSC conductance. 5. In the presence of 1 mM [Mg2+]o, GABAA receptor-mediated inhibition had to decrease to 17 +/- 11% of control values, in the presence of 4-7 microM bicuculline, to reach threshold for epileptic activity. 6. These data demonstrate a postsynaptic decrease in GABAA receptor-mediated inhibition in the in vitro low magnesium model of epilepsy. We propose that the apparent leaching of intracellular Mg2+ ([Mg2+]i) from cells leads to loss of ATP and consequent partial dephosphorylation of the GABAA receptor and that this is exacerbated by epileptic activity.

Animals↗
PubMed1995

Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation.

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.

Action Potentials↗
PubMed1995

Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein.

The prion protein (PrP) is central to the aetiology of the prion diseases, transmissible neurodegenerative conditions of humans and animals. PrP null mice show abnormalities of synaptic neurophysiology, in particular weakened GABAA receptor-mediated fast inhibition and impaired long-term potentiation in the hippocampus. Here we demonstrate that this PrP null phenotype is rescued in mice with a high copy number of a transgene encoding human PrP but not in low copy number mice, confirming the specificity of the phenotype for loss of function of PrP. The ability of human PrP to compensate for loss of murine PrP will allow direct study of the functional consequences of the 18 human PrP mutations, which cause the inherited prion diseases; this phenotype can now form the basis of the first functional assay for PrP.

Animals↗