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Epilepsy has been historically seen as a functional brain disorder associated with excessive synchronization of large neuronal populations leading to a hypersynchronous state. Recent evidence showed that epileptiform phenomena, particularly seizures, result from complex interactions between neuronal networks characterized by heterogeneity of neuronal firing and dynamical evolution of synchronization. Desynchronization is often observed preceding seizures or during their early stages; in contrast, high levels of synchronization observed towards the end of seizures may facilitate termination. In this review we discuss cellular and network mechanisms responsible for such complex changes in synchronization. Recent work has identified cell-type-specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non-local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non-firing neurons active in seizures. These recent advances have challenged long-established views and are leading to a more rigorous and realistic understanding of the pathophysiology of epilepsy.

How seizures start is a major question in epilepsy research. Preictal EEG changes occur in both human patients and animal models, but their underlying mechanisms and relationship with seizure initiation remain unknown. Here we demonstrate the existence, in the hippocampal CA1 region, of a preictal state characterized by the progressive and global increase in neuronal activity associated with a widespread buildup of low-amplitude high-frequency activity (HFA) (>100 Hz) and reduction in system complexity. HFA is generated by the firing of neurons, mainly pyramidal cells, at much lower frequencies. Individual cycles of HFA are generated by the near-synchronous (within approximately 5 ms) firing of small numbers of pyramidal cells. The presence of HFA in the low-calcium model implicates nonsynaptic synchronization; the presence of very similar HFA in the high-potassium model shows that it does not depend on an absence of synaptic transmission. Immediately before seizure onset, CA1 is in a state of high sensitivity in which weak depolarizing or synchronizing perturbations can trigger seizures. Transition to seizure is characterized by a rapid expansion and fusion of the neuronal populations responsible for HFA, associated with a progressive slowing of HFA, leading to a single, massive, hypersynchronous cluster generating the high-amplitude low-frequency activity of the seizure.

Neuronal population oscillations in the hippocampus have an important effect in the information processing in the brain and the generation of epileptic seizures. In this paper, we investigate the neuronal population oscillations in the hippocampus of epileptic rats in vivo using an empirical mode decomposition (EMD) method. A neuronal population oscillation can be decomposed into several relaxation oscillations, which possess a recovery and release phase, with the different frequencies that ranges from 0 to 600 Hz. The natures of relaxation oscillations at the pre-ictal, seizure onset and ictal states are distinctly different. The analysis of relaxation oscillations show that the gamma wave is a lead relaxation oscillation at the pre-ictal stage, then it moves to beta oscillation or theta oscillation while the ictal stage starts; the fast relaxation oscillations are associated with the slow relaxation oscillations in the CA1 or CA3, in particular, the fast relaxation oscillations are associated on the recovery phase of the slow relaxation oscillations during the pre-ictal interval, however move to the release phase of the slow relaxation oscillations during the ictal interval. Comparison of the relaxation oscillations in CA1 and CA3 shows that the neurons in the CA1 are more active during the epileptic seizures than during the pre-ictal stage. These findings demonstrate that this method is very helpful to decompose neuronal population for understanding the underlying mechanism of epileptic seizures.

The purpose of the present paper is to develop a method, based on equal-time correlation, correlation matrix analysis and surrogate resampling, that is able to quantify and describe properties of synchronization of population neuronal activity recorded simultaneously from multiple sites. Initially, Lorenz-type oscillators were used to model multiple time series with different patterns of synchronization. Eigenvalue and eigenvector decomposition was then applied to identify "clusters" of locally synchronized activity and to calculate a "global synchronization index." This method was then applied to multichannel data recorded from an in vitro model of epileptic seizures. The results demonstrate that this novel method can be successfully used to analyze synchronization between multiple neuronal population series.

The CA1 region of the rat hippocampal slice generates spontaneous electrographic seizures (field bursts) when exposed to ACSF containing < or = 0.2 mM calcium. It has been proposed that, particularly during the early part of a field burst, synchronised activity in small independent aggregates of neurons results in low amplitude irregular population spikes and subsequent fusion of aggregates generates high amplitude, regular discharging spikes. In the present experiments, we have tested the hypothesis that progression from aggregate formation to aggregate fusion requires a critical mass of participating neurons. We found that isolated CA1 segments >2 mm are still able to generate high amplitude, regular discharging population spikes, but when segment length is reduced to 1-2 mm, only 29% generate spikes with these characteristics; in the remainder, the field burst shows a DC shift+/-low amplitude irregular population spikes. No field bursts were seen in segments < 0.7 mm or in 50% of those 0.7-1 mm in length (in the remaining 50%, only the DC component of the field burst was present). Exposing 1-2 mm segments to hypo-osmolar perfusate induced a return of high amplitude rhythmic discharging population spikes in the field burst. We interpret these observations by indicating that progression from aggregate formation to aggregate fusion requires a critical neuronal mass and can be enhanced by reducing osmolarity of the perfusate.

Population spikes vary in size during prolonged epileptic ("ictal") discharges, indicating variations in neuronal synchronization. Here we investigate the role of changes in tissue electrical resistivity in this process. We used the rat hippocampal slice, low-Ca(2+) model of epilepsy and measured changes in pyramidal layer extracellular resistance during the course of electrographic seizures. During each burst, population spike frequency decreased, whereas amplitude and spatial synchronization increased; after the main discharge, there could be brief secondary discharges that, in contrast with those in the primary discharge, started with high-amplitude population spikes. Mean resistivity increased from 1,231 Omega.cm immediately before the burst to a maximum of 1,507 Omega.cm during the burst. There was no significant increase during the first 0.5-1 s of the field burst, but resistance then increased (tau approximately 5 s), reaching its peak at the end of the burst, and then decayed slowly (tau approximately 10 s). In further experiments, we modulated the efficacy of electrical field effects by changing perfusate osmolarity. Reducing osmolarity by 40-70 mOsm increased preburst resistivity by 19%; it reduced minimum population spike frequency (x0.6-0.7) and increased both maximum population spike amplitude (x1.5-2.3) and spatial synchronization (x1.4-2.5, cross-correlation over 0.5 mm) during bursts. Increasing osmolarity by 20-40 mOsm had the opposite effects. These results suggest that, during each field burst, field effects between neurons gradually become more effective as cells swell, thereby modulating burst dynamics and facilitating the rapid synchronization of secondary discharges.

Epileptic seizures are associated with neuronal hyperactivity. Here, however, we investigated whether continuous neuronal firing is necessary to maintain electrographic seizures. We studied a class of "low-Ca2+" ictal epileptiform bursts, induced in rat hippocampal slices, that are characterized by prolonged (2-15 s) interruptions in population spike generation. We found that, during these interruptions, neuronal firing was suppressed rather than desynchronized. Intracellular current injection, application of extracellular uniform electric fields, and antidromic stimulation showed that the source of action potential disruption was depolarization block. The duration of the extracellular potassium transients associated with each ictal burst was not affected by disruptions in neuronal firing. Application of phenytoin or veratridine indicated a critical role for the persistent sodium current in maintaining depolarization block. Our results show that continuous neuronal firing is not necessary for the maintenance of experimental electrographic seizures.

High-frequency activity often precedes seizure onset. We found that electrographic seizures, induced in vitro using the low-Ca(2+) model, start with high-frequency (>150 Hz) activity that then decreases in frequency while increasing in amplitude. Multichannel and unit recordings showed that the mechanism of this transition was the progressive formation of larger neuronal aggregates. Thus the apparent high-frequency activity, at seizure onset, can reflect the simultaneous recording of several slower firing aggregates. Aggregate formation rate can be accelerated by reducing osmolarity. Because synaptic transmission is blocked when extracellular Ca(2+) is reduced, nonsynaptic mechanisms (gap junctions, field effects) must be sufficient for aggregate formation and recruitment.

Exposure to extremely low frequency electric and magnetic fields will induce electric fields and currents within the body, but these are almost always much lower than those that can stimulate peripheral nerve tissue. Guidance on exposure to such fields has been published by NRPB and ICNIRP, which is based on the avoidance of acute effects in the central nervous system. Weak electric field effects, below action potential thresholds, have been demonstrated in vitro in brain slice preparations; thresholds can be estimated to be above about 1 mV mm(-1) (around 100 mA m(-2), taking a brain tissue conductivity of around 0.1 S m(-1)), depending on stimulus conditions. Some studies suggest possible effects at lower induced field strengths. The intact nervous system might be expected to be more sensitive to induced electric fields and currents than in vitro preparations, due to a higher level of spontaneous activity and a greater number of interacting neurons. There is good evidence that electrically excitable cells in the retina can be affected in vivo by induced currents as low as 10 mA m(-2). It has been suggested that induced current densities above 10 mA m(-2) may have effects on other central nervous system functions but few studies have been carried out. Further research in experimental animals using both in vitro and in vivo approaches is needed to clarify this issue.

Key points The synchronisation of neuronal activity at gamma frequencies (30-100 Hz) could determine the effectiveness of neuronal communication., Gamma oscillations in the CA1 region of the hippocampus in vitro was thought to be dependent on gamma oscillations generated in area CA3, but in vivo CA1 can generate gamma oscillations independently., In this study we found that activating acetylcholine receptors induced stable gamma oscillations in the CA1 local network isolated in slices in vitro that were faster than those in CA3, but relied on similar neuronal circuitry involving feedback inhibition., Gamma frequency inputs from CA3 (spontaneous in intact hippocampal slices or stimulated in isolated CA1) can suppress the local fast gamma oscillation in CA1 and force it to adopt the slower CA3 oscillation through feed-forward inhibition., This modulation could allow CA1 to alternate between effective communication with the entorhinal cortex and CA3, which may regulate memory encoding and memory recall phases., Abstract Hippocampal gamma oscillations have been associated with cognitive functions including navigation and memory encoding/retrieval. Gamma oscillations in area CA1 are thought to depend on the oscillatory drive from CA3 (slow gamma) or the entorhinal cortex (fast gamma). Here we show that the local CA1 network can generate its own fast gamma that can be suppressed by slow gamma-paced inputs from CA3. Moderate acetylcholine receptor activation induces fast (45 ± 1 Hz) gamma in rat CA1 minislices and slow (33 ± 1 Hz) gamma in CA3 minislices in vitro. Using pharmacological tools, current-source density analysis and intracellular recordings from pyramidal cells and fast-spiking stratum pyramidale interneurons, we demonstrate that fast gamma in CA1 is of the pyramidal-interneuron network gamma (PING) type, with the firing of principal cells paced by recurrent perisomal IPSCs. The oscillation frequency was only weakly dependent on IPSC amplitude, and decreased to that of CA3 slow gamma by reducing IPSC decay rate or reducing interneuron activation through tonic inhibition of interneurons. Fast gamma in CA1 was replaced by slow CA3-driven gamma in unlesioned slices, which could be mimicked in CA1 minislices by sub-threshold 35 Hz Schaffer collateral stimulation that activated fast-spiking interneurons but hyperpolarised pyramidal cells, suggesting that slow gamma frequency CA3 outputs can suppress the CA1 fast gamma-generating network by feed-forward inhibition and replaces it with a slower gamma oscillation driven by feed-forward inhibition. The transition between the two gamma oscillation modes in CA1 might allow it to alternate between effective communication with the medial entorhinal cortex and CA3, which have different roles in encoding and recall of memory. [ABSTRACT FROM AUTHOR]

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Prion protein (PrP) is a normal component of neurons, which confers susceptibility to prion diseases. Despite its evolutionary conservation, its normal function remains controversial. PrP-deficient (Prnp0/0) mice have weaker afterhyperpolarizations (AHPs) in cerebellar and hippocampal neurons. Here we show that the AHP impairment in hippocampal CA1 pyramidal cells is selective for the slow AHP, and is not caused by an impairment of either voltage-gated Ca2+ channels or Ca2+-activated K+ channels. Instead, Prnp0/0 neurons have twofold to threefold stronger Ca2+ buffering and double the Ca2+ extrusion rate. In Prnp0/0 neurons thapsigargin abolished the stronger Ca2+ buffering and extrusion, and thapsigargin or cyclopiazonic acid abolished the weakening of the slow AHPs. These data implicate sarcoplasmic/endoplasmic reticulum calcium ATPase in the enhanced Ca2+ buffering, and extrusion into the endoplasmic reticulum, which contains substantial amounts of PrP in wild-type mice. Altered Ca2+ homeostasis can explain several phenotypes identified in Prnp0/0 mice. [ABSTRACT FROM AUTHOR]

The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein levels. Pharmacological inhibition of NR2B function impaired synaptic facilitation in area cornus ammonicus region 3 (CA3) in acute hippocampal slices derived from caMEK1-expressing mice and abrogated epilepsy in vivo. In addition, expression of caMEK1 caused phosphorylation of the transcription factor, cAMP response element-binding protein (CREB) and increased transcription of ephrinB2. EphrinB2 overexpression resulted in increased NR2B tyrosine phosphorylation, which was essential for caMEK1-induced epilepsy in vivo, since conditional inactivation of ephrinB2 greatly reduced seizure frequency in caMEK1 transgenic mice. Therefore, our study identifies a mechanism of epileptogenesis that links MAP kinase to Eph/Ephrin and NMDA receptor signalling. [ABSTRACT FROM AUTHOR]

Purpose: Epileptiform burst-firing can occur in hippocampal area CA1 where recurrent excitation is relatively weak and recurrent inhibition strong. Recent observations suggest that recurrent inhibition can transform into recurrent excitation because of collapse of the chloride gradient. Here we assess the role of potassium in this epileptogenic transformation. Methods: Extracellular field potential recordings, combined with either intracellular recordings from pyramidal neurons or extracellular potassium concentration recordings, were made in vitro from isolated CA1 minislices cut from the rat hippocampus and in vivo from area CA1 in urethane-anesthetized rats. Burst responses were evoked by 5-Hz alveus stimulation. Results: The 5-Hz alveus stimulation in vitro caused a transient period of burst responses that was associated with a transient increase in synaptic input in stratum oriens and a transient shift of the reversal potential of the synaptic potential. These changes were related to the transient increase in extracellular potassium concentration in stratum oriens. Observations in vivo confirmed the relation between bursting and extracellular potassium concentration in stratum oriens. Conclusions: Use-dependent increase of extracellular potassium concentration in stratum oriens facilitates the collapse of the chloride gradient in the basal dendrites and transforms γ-aminobutyric acid (GABA)ergic inhibition into GABAergic excitation, giving rise to burst firing. Improvement of intracellular chloride homeostasis or extracellular potassium homeostasis could reduce epileptogenicity. [ABSTRACT FROM AUTHOR]

Tetanic stimulation of axons terminating in the CA1 region of the hippocampus induces oscillations in the gamma-to-beta frequency band (13–100 Hz) and can induce long-term potentiation (LTP). The rapid pyramidal cell discharge is driven by a mainly GABAA-receptor-mediated slow depolarization and entrained mainly through ephaptic interactions. This study tests whether cellular compartmentalization can explain how cells, despite severely reduced input resistance, can still fire briskly and have IPSPs superimposed on the slow GABAergic depolarization, and whether this behaviour occursin vivo. Oscillations induced in CA1in vitroby tetanic stimulation of the stratum radiatum or oriens were analysed using intracellular and multichannel field potentials along the cell axis. Layer-specific effects of focal application of bicuculline indicate that the GABAergic depolarization is concentrated on tetanized dendrites. Current-source density analysis and characteristics of partial spikes indicate that early action potentials are initiated in the proximal nontetanized dendrite but cannot invade the tetanized dendrite, where recurrent EPSPs and evoked IPSPs were largely suppressed. As the oscillation progresses, IPSPs recover and slow the neuronal firing toβ frequencies, with a small subpopulation of neurons continuing to fire atγ frequency. Carbonic anhydrase dependence, threshold intensity, frequency, field strength and spike initiation/propagation of tetanus-evoked oscillations in urethane-anaesthetized rats, validate our observationsin vitro, and show that these mechanisms operate in healthy tissue. However, the disrupted electrophysiology of the tetanized dendrites will disable normal information processing, has implications for LTP induction and is likely to play a role in pathological synchronization as found during epileptic discharges. [ABSTRACT FROM AUTHOR]