Liset Menendez de la Prida

Mechanisms of physiological and epileptic HFO generation

High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and networks, investigated in a variety of experimental in vitro and in vivo models. Diverse mechanisms are described, from intrinsic membrane oscillations to network processes involving different types of synaptic interactions, gap junctions and ephaptic coupling. HFOs with similar frequency ranges can differ considerably in their physiological mechanisms. The fact that in most cases the combination of intrinsic neuronal membrane oscillations and synaptic circuits are necessary to sustain network oscillations is emphasized. Evidence for pathological HFOs, particularly fast ripples, in experimental models of epilepsy and in human epileptic patients is scrutinized. The underlying mechanisms of fast ripples are examined both in the light of animal observations, in vivo and in vitro, and in epileptic patients, with emphasis on single cell dynamics. Experimental observations and computational modeling have led to hypotheses for these mechanisms, several of which are considered here, namely the role of out-of-phase firing in neuronal clusters, the importance of strong excitatory AMPA-synaptic currents and recurrent inhibitory connectivity in combination with the fast time scales of IPSPs, ephaptic coupling and the contribution of interneuronal coupling through gap junctions. The statistical behaviour of fast ripple events can provide useful information on the underlying mechanism and can help to further improve classification of the diverse forms of HFOs.

Reduced Spike-Timing Reliability Correlates with the Emergence of Fast Ripples in the Rat Epileptic Hippocampus

Ripples are sharp-wave-associated field oscillations (100-300 Hz) recorded in the hippocampus during behavioral immobility and slow-wave sleep. In epileptic rats and humans, a different and faster oscillation (200-600 Hz), termed fast ripples, has been described. However, the basic mechanisms are unknown. Here, we propose that fast ripples emerge from a disorganized ripple pattern caused by unreliable firing in the epileptic hippocampus. Enhanced synaptic activity is responsible for the irregular bursting of CA3 pyramidal cells due to large membrane potential fluctuations. Lower field interactions and a reduced spike-timing reliability concur with decreased spatial synchronization and the emergence of fast ripples. Reducing synaptically driven membrane potential fluctuations improves both spike-timing reliability and spatial synchronization and restores ripples in the epileptic hippocampus. Conversely, a lower spike-timing reliability, with reduced potassium currents, is associated with ripple shuffling in normal hippocampus. Therefore, fast ripples may reflect a pathological desynchronization of the normal ripple pattern.

Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy

The mechanisms involved in the transition to an epileptic seizure remain unclear. To examine them, we used tissue slices from human subjects with mesial temporal lobe epilepsies. Ictal-like discharges were induced in the subiculum by increasing excitability along with alkalinization or low Mg2+. During the transition, distinct pre-ictal discharges emerged concurrently with interictal events. Intracranial recordings from the mesial temporal cortex of subjects with epilepsy revealed that similar discharges before seizures were restricted to seizure onset sites. In vitro, pre-ictal events spread faster and had larger amplitudes than interictal discharges and had a distinct initiation site. These events depended on glutamatergic mechanisms and were preceded by pyramidal cell firing, whereas interneuron firing preceded interictal events that depended on both glutamatergic and depolarizing GABAergic transmission. Once established, recurrence of these pre-ictal discharges triggered seizures. Thus, the subiculum supports seizure generation, and the transition to seizure involves an emergent glutamatergic population activity.

Threshold Behavior in the Initiation of Hippocampal Population Bursts

Hippocampal population discharges such as sharp waves, epileptiform firing, and GDPs recur at long and variable intervals. The mechanisms for their precise timing are not well understood. Here, we show that population bursts in the disinhibited CA3 region are initiated at a threshold level of population firing after recovery from a previous event. Each population discharge follows an active buildup period when synaptic traffic and cell firing increase to threshold levels. Single-cell firing can advance burst onset by increasing population firing to suprathreshold values. Population synchrony is suppressed when threshold frequencies cannot be reached due to reduced cellular excitability or synaptic efficacy. Reducing synaptic strength reveals partially synchronous population bursts that are curtailed by GABA(B)-mediated conductances. Excitatory glutamatergic transmission and delayed GABA(B)-mediated signals have opposing feedback effects on CA3 cell firing and so determine threshold behavior for population synchrony.

Emergent Dynamics of Fast Ripples in the Epileptic Hippocampus

Fast ripples are a type of transient high-frequency oscillations recorded from the epileptogenic regions of the hippocampus and the temporal cortex of epileptic humans and rodents. These events presumably reflect hypersynchronous bursting of pyramidal cells. However, the oscillatory spectral content of fast ripples varies from 250 to 800 Hz, well above the maximal firing frequency of most hippocampal pyramidal neurons. How such high-frequency oscillations are generated is therefore unclear. Here, we combine computational simulations of fast ripples with multisite and juxtacellular recordings in vivo to examine the underlying mechanisms in the hippocampus of epileptic rats. We show that populations of bursting cells firing individually at 100–400 Hz can create fast ripples according to two main firing regimes: (1) in-phase synchronous firing resulting in “pure” fast ripples characterized by single spectral peaks that reflect single-cell behavior and (2) out-of-phase firing that results in “emergent” fast ripples. Using simulations, we found that fast ripples generated under these two different regimes can be quantitatively separated by their spectral characteristics, and we took advantage of this separability to examine their dynamics in vivo. We found that in-phase firing can reach frequencies up to 300 Hz in the CA1 and up to 400 Hz in the dentate gyrus. The organization of out-of-phase firing is determined by firing delays between cells discharging at low frequencies. The two firing regimes compete dynamically, alternating randomly from one fast ripple event to the next, and they reflect the functional dynamic organization of the different regions of the hippocampus.

Synchronization Clusters of Interictal Activity in the Lateral Temporal Cortex of Epileptic Patients: Intraoperative Electrocorticographic Analysis

Objective: Drug‐resistant temporal lobe epilepsy (TLE) can be treated by tailored surgery guided by electrocorticography (ECoG). Although its value is still controversial, ECoG activity can provide continuous information on intracortical interactions that may be useful to understand the pathophysiology of TLE. The goal of this study is to characterize local interactions in multichannel ECoG recordings of the lateral cortex of TLE patients using three synchronization measures and to link this information with surgical outcome.

Loss of COUP-TFI Alters the Balance between Caudal Ganglionic Eminence- and Medial Ganglionic Eminence-Derived Cortical Interneurons and Results in Resistance to Epilepsy

In rodents, cortical interneurons originate from the medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) according to precise temporal schedules. The mechanisms controlling the specification of CGE-derived interneurons and their role in cortical circuitry are still unknown. Here, we show that COUP-TFI expression becomes restricted to the dorsal MGE and CGE at embryonic day 13.5 in the basal telencephalon. Conditional loss of function of COUP-TFI in subventricular precursors and postmitotic cells leads to a decrease of late-born, CGE-derived, VIP (vasoactive intestinal peptide)- and CR (calretinin)-expressing bipolar cortical neurons, compensated by the concurrent increase of early-born MGE-derived, PV (parvalbumin)-expressing interneurons. Strikingly, COUP-TFI mutants are more resistant to pharmacologically induced seizures, a phenotype that is dependent on GABAergic signaling. Together, our data indicate that COUP-TFI controls the delicate balance between MGE- and CGE-derived cortical interneurons by regulating intermediate progenitor divisions and ultimately affecting the activity of the cortical inhibitory circuitry.

Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples

Sharp-wave ripples represent a prominent synchronous activity pattern in the mammalian hippocampus during sleep and immobility. GABAergic interneuronal types are silenced or fire during these events, but the mechanism of pyramidal cell (PC) participation remains elusive. We found opposite membrane polarization of deep (closer to stratum oriens) and superficial (closer to stratum radiatum) rat CA1 PCs during sharp-wave ripples. Using sharp and multi-site recordings in combination with neurochemical profiling, we observed a predominant inhibitory drive of deep calbindin (CB)-immunonegative PCs that contrasts with a prominent depolarization of superficial CB-immunopositive PCs. Biased contribution of perisomatic GABAergic inputs, together with suppression of CA2 PCs, may explain the selection of CA1 PCs during sharp-wave ripples. A deep-superficial gradient interacted with behavioral and spatial effects to determine cell participation during sleep and awake sharp-wave ripples in freely moving rats. Thus, the firing dynamics of hippocampal PCs are exquisitely controlled at subcellular and microcircuit levels in a cell type–selective manner.

Specific impairment of "what-where-when" episodic-like memory in experimental models of temporal lobe epilepsy.

Episodic memory deficit is a common cognitive disorder in human temporal lobe epilepsy (TLE). However, no animal model of TLE has been shown to specifically replicate this cognitive dysfunction, which has limited its translational appeal. Here, using a task that tests for nonverbal correlates of episodic-like memory in rats, we show that kainate-treated TLE rats exhibit a selective impairment of the “what-where-when” memory while preserving other forms of hippocampal-dependent memories. Assisted by multisite silicon probes, we recorded from the dorsal hippocampus of behaving animals to control for seizure-related factors and to look for electrophysiological signatures of cognitive impairment. Analyses of hippocampal local field potentials showed that both the power of theta rhythm and its coordination across CA1 and the DG—measured as theta coherence and phase locking—were selectively disrupted. This disruption represented a basal condition of the chronic epileptic hippocampus that was linked to different features of memory impairment. Theta power was more correlated with the spatial than with the temporal component of the task, while measures of theta coordination correlated with the temporal component. We conclude that episodic-like memory, as tested in the what-where-when task, is specifically affected in experimental TLE and that the impairment of hippocampal theta activity might be central to this dysfunction.

Cellular mechanisms of high frequency oscillations in epilepsy: on the diverse sources of pathological activities.

A major goal in epilepsy research is to understand the cellular basis of pathological forms of network oscillations, particularly those classified as high-frequency activity. What are the underlying mechanisms, and how do they arise? The topic of this review is the pattern of high-frequency oscillations that have been recorded in epileptic tissue, and how they might differ from physiological activity. We discuss recent experimental and clinical data with a major focus on the diverse sources of extracellular signals and the contribution of different neuronal populations, including GABAergic interneurons and glutamatergic principal cells.