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The neocortex is highly susceptible to metabolic dysfunction. When exposed to global ischemia or anoxia, it suffers a slowly propagating wave of collective neuronal depolarization that ultimately impairs its structure and function. While the molecular signature of anoxic depolarization (AD) is well documented, little is known about the brain states that precede and follow AD onset. Here, by means of multisite extracellular local field potentials and intracellular recordings from identified pyramidal cells, we investigated the laminar expression of cortical activities induced by transient anoxia in rat primary somatosensory cortex. Soon after the interruption of brain oxygenation, we observed a well-organized sequence of stereotyped activity patterns across all cortical layers. This sequence included an initial period of beta-gamma activity, rapidly replaced by delta-theta oscillations followed by a decline in all spontaneous activites, marking the entry into a sustained period of electrical silence. Intracellular recordings revealed that cortical pyramidal neurons were depolarized and highly active during high-frequency activity, became inactive and devoid of synaptic potentials during the isoelectric state, and showed subthreshold composite synaptic depolarizations during the low-frequency period. Contrasting with the strong temporal coherence of pre-AD activities along the vertical axis of the cortical column, the onset of AD was not uniform across layers. AD initially occurred in layer 5 or 6 and then propagated bidirectionally in the upward and downward direction. Conversely, the post-anoxic waves that indicated the repolarization of cortical neurons upon brain reoxygenation did not exhibit a specific spatio-temporal profile. Pyramidal neurons from AD initiation site had a more depolarized resting potential and higher spontaneous firing rate compared to superficial cortical cells. We also found that the propagation pattern of AD was reliably reproduced by focal injection of an inhibitor of sodium‑potassium ATPases, suggesting that cortical AD dynamics could reflect layer-dependent variations in cellular metabolic regulations., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinically, and legally, death is considered a well-defined state of the organism characterized, at least, by a complete and irreversible cessation of brain activities and functions. According to this pragmatic approach, the moment of death is implicitly represented by a discrete event from which all cerebral processes abruptly cease. However, a growing body of experimental and clinical evidence has demonstrated that cardiorespiratory failure, the leading cause of death, causes complex time-dependent changes in neuronal activity that can lead to death but also be reversed with successful resuscitation. This review synthesizes our current knowledge of the succeeding alterations in brain activities that accompany the dying and resuscitation processes. The anoxia-dependent brain defects that usher in a process of potential death successively include: (1) a set of changes in electroencephalographic (EEG) and neuronal activities, (2) a cessation of brain spontaneous electrical activity (isoelectric state), (3) a loss of consciousness whose timing in relation to EEG changes remains unclear, (4) an increase in brain resistivity, caused by neuronal swelling, concomitant with the occurrence of an EEG deviation reflecting the neuronal anoxic insult (the so-called "wave of death," or "terminal spreading depolarization"), followed by, (5) a terminal isoelectric brain state leading to death. However, a timely restoration of brain oxygen supply-or cerebral blood flow-can initiate a mirrored sequence of events: a repolarization of neurons followed by a re-emergence of neuronal, synaptic, and EEG activities from the electrocerebral silence. Accordingly, a recent study has revealed a new death-related brain wave: the "wave of resuscitation," which is a marker of the collective recovery of electrical properties of neurons at the beginning of the brain's reoxygenation phase. The slow process of dying still represents a terra incognita, during which neurons and neural networks evolve in uncertain states that remain to be fully understood. As current event-based models of death have become neurophysiologically inadequate, I propose a new mixed (event-process) model of death and resuscitation. It is based on a detailed description of the different phases that succeed each other in a dying brain, which are generally described separately and without mechanistic linkage, in order to integrate them into a continuum of declining brain activity. The model incorporates cerebral twilight zones (with still unknown neuronal and synaptic processes) punctuated by two characteristic cortical waves providing real-time biomarkers of death- and resuscitation., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Charpier.)

Objective: It is unknown whether ultrasound-induced blood-brain barrier (BBB) disruption can promote epileptogenesis and how BBB integrity changes over time after sonication., Methods: To gain more insight into the safety profile of ultrasound (US)-induced BBB opening, we determined BBB permeability as well as histological modifications in C57BL/6 adult control mice and in the kainate (KA) model for mesial temporal lobe epilepsy in mice after sonication with low-intensity pulsed ultrasound (LIPU). Microglial and astroglial changes in ipsilateral hippocampus were examined at different time points following BBB disruption by respectively analyzing Iba1 and glial fibrillary acidic protein immunoreactivity. Using intracerebral EEG recordings, we further studied the possible electrophysiological repercussions of a repeated disrupted BBB for seizure generation in nine non-epileptic mice., Results: LIPU-induced BBB opening led to transient albumin extravasation and reversible mild astrogliosis, but not to microglial activation in the hippocampus of non-epileptic mice. In KA mice, the transient albumin extravasation into the hippocampus mediated by LIPU-induced BBB opening did not aggravate inflammatory processes and histologic changes that characterize the hippocampal sclerosis. Three LIPU-induced BBB opening did not induce epileptogenicity in non-epileptic mice implanted with depth EEG electrodes., Conclusion: Our experiments in mice provide persuasive evidence of the safety of LIPU-induced BBB opening as a therapeutic modality for neurological diseases., Competing Interests: Declaration of competing interest A.C. developed the ultrasound technology used in this study and deposited the patent related to this invention. A.C. is shareholder and consultant for CarThera. The other authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Autoimmune encephalitis (AIE) associated with antibodies directed against the leucine-rich glioma inactivated 1 (LGI1) protein is the second most common AIE and is responsible for deleterious neocortical and limbic epileptic seizures. Previous studies demonstrated a pathogenic role of anti-LGI1 antibodies via alterations in the expression and function of Kv1 channels and AMPA receptors. However, the causal link between antibodies and epileptic seizures has never been demonstrated. Here, we attempted to determine the role of human anti-LGI1 autoantibodies in the genesis of seizures by analyzing the impact of their intracerebral injection in rodents. Acute and chronic injections were performed in rats and mice in the hippocampus and primary motor cortex, the two main brain regions affected by the disease. Acute infusion of CSF or serum IgG of anti-LGI1 AIE patients did not lead to the emergence of epileptic activities, as assessed by multisite electrophysiological recordings over a 10 h period after injection. A chronic 14 d injection, coupled with continuous video-EEG monitoring, was not more effective. Overall, these results demonstrate that acute and chronic injections of CSF or purified IgG from LGI1 patients are not able to generate epileptic activity by themselves in the different animal models tested., Competing Interests: V.N. reports personal fees from UCB, Liva Nova, and EISAI, outside of the submitted work. The authors declare no other competing financial interests., (Copyright © 2023 Baudin et al.)

Magnetic brain stimulation is a promising treatment for neurological and psychiatric disorders. However, a better understanding of its effects at the individual neuron level is essential to improve its clinical application. We combined focal low-intensity repetitive transcranial magnetic stimulation (LI-rTMS) to the rat somatosensory cortex with intracellular recordings of subjacent pyramidal neurons in vivo. Continuous 10 Hz LI-rTMS reliably evoked firing at ∼4-5 Hz during the stimulation period and induced durable attenuation of synaptic activity and spontaneous firing in cortical neurons, through membrane hyperpolarization and a reduced intrinsic excitability. However, inducing firing in individual neurons by repeated intracellular current injection did not reproduce the effects of LI-rTMS on neuronal properties. These data provide a novel understanding of mechanisms underlying magnetic brain stimulation showing that, in addition to inducing biochemical plasticity, even weak magnetic fields can activate neurons and enduringly modulate their excitability. KEY POINTS: Repetitive transcranial magnetic stimulation (rTMS) is a promising technique to alleviate neurological and psychiatric disorders caused by alterations in cortical activity. Our knowledge of the cellular mechanisms underlying rTMS-based therapies remains limited. We combined in vivo focal application of low-intensity rTMS (LI-rTMS) to the rat somatosensory cortex with intracellular recordings of subjacent pyramidal neurons to characterize the effects of weak magnetic fields at single cell level. Ten minutes of LI-rTMS delivered at 10 Hz reliably evoked action potentials in cortical neurons during the stimulation period, and induced durable attenuation of their intrinsic excitability, synaptic activity and spontaneous firing. These results help us better understand the mechanisms of weak magnetic stimulation and should allow optimizing the effectiveness of stimulation protocols for clinical use., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Autoimmune encephalitis associated with antibodies directed against the leucine-rich glioma inactivated 1 (LGI1) protein is responsible for specific tonic-dystonic motor seizures. Although dysfunctions in neuronal excitability have been associated with anti-LGI1 autoantibodies, their relation to seizures remain inconclusive. We developed a new in vivo experimental rat model to determine whether inhibition of Kv1.1 channels by dentrotoxin-K (DTX) in the primary motor cortex (M1) could recapitulate the human seizures and to elucidate their subtending cortical mechanisms. Comparing electro-clinical features of DTX-induced seizures in rats with those recorded from a cohort of anti-LGI1 encephalitis patients revealed striking similarities in their electroencephalographic (EEG) signature, frequency of recurrence and semiology. By combining multi-site extracellular and intracellular recordings of M1 pyramidal neurons in DTX rats, we demonstrated that the blockade of Kv1.1 channels induced a sequence of changes in neuronal excitability and synaptic activity, leading to massive suprathreshold membrane depolarizations underlying the paroxysmal EEG activity. Our results suggest the central role of Kv1.1 channels disruption in the emergence of anti-LGI1-associated seizures and suggest that this new rodent model could serve future investigations on ictogenesis in autoimmune encephalitis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Key Points: The neuronal and network properties that persist during an isoelectric coma remain largely unknown.  We developed a new in vivo rat model to assess cell excitability and sensory responsiveness in the thalamo-cortical pathway during an isoflurane-induced isoelectric brain state.  The isoelectric electrocorticogram reflected a complete interruption of spontaneous synaptic and firing activities in cortical and thalamic neurons.  Cell excitability and sensory responses in the thalamo-cortical network persisted at a reduced level in the isoelectric condition and returned to control values after resumption of background brain activity.  These findings could lead to a reassessment of the functional status of the drug-induced isoelectric state: a latent state in which individual neurons and networks retain to some extent the ability of being activated by external inputs., Abstract: The neuronal and network properties that persist in an isoelectric brain completely deprived of spontaneous electrical activity remain largely unexplored. Here, we developed a new in vivo rat model to examine cell excitability and sensory responsiveness in somatosensory thalamo-cortical networks during the interruption of endogenous brain activity induced by high doses of isoflurane. Electrocorticograms (ECoGs) from the barrel cortex were captured simultaneously with either intracellular recordings of subjacent cortical pyramidal neurons or extracellular records of the related thalamo-cortical neurons. Isoelectric ECoG periods reflected the disappearance of spontaneous synaptic and firing activities in cortical and thalamic neurons. This was associated with a sustained membrane hyperpolarization and a reduced intrinsic excitability in deep-layer cortical neurons, without significant changes in their membrane input resistance. Concomitantly, we found that whisker-evoked potentials in the ECoG and synaptic responses in cortical neurons were attenuated in amplitude and increased in latency. Impaired responsiveness in the barrel cortex paralleled with a lowering of the sensory-induced firing in thalamic cells. The return of endogenous brain electrical activities, after reinstatement of a control isoflurane concentration, led to the recovery of cortical neurons excitability and sensory responsiveness. These findings demonstrate the persistence of a certain level of cell excitability and sensory integration in the isoelectric state and the full recovery of cortico-thalamic functions after restoration of internal cerebral activities., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

The striatum is involved in the completion and optimization of sensorimotor tasks. In rodents, its dorsolateral part receives converging glutamatergic corticostriatal (CS) inputs from whisker-related primary somatosensory (S1) and motor (M1) cortical areas, which are interconnected at the cortical level. Although it has been demonstrated that the medium-spiny neurons (MSNs) from the dorsolateral striatum process sensory information from the whiskers via the S1 CS pathway, the functional impact of the corresponding M1 CS inputs onto the same striatal neurons remained unknown. Here, by combining in vivo S1 electrocorticogram with intracellular recordings from somatosensory MSNs in the rat, we first confirmed the heterogeneity of striatal responsiveness to whisker stimuli, encompassing MSNs responding exclusively by subthreshold synaptic depolarizations, MSNs exhibiting sub- and suprathreshold responses over successive stimulations, and non-responding cells. All recorded MSNs also exhibited clear-cut monosynaptic depolarizing potentials in response to electrical stimulations of the corresponding ipsilateral M1 cortex, which were efficient to fire striatal cells. Since M1-evoked responses in MSNs could result from the intra-cortical recruitment of S1 CS neurons, we performed intracellular recordings of S1 pyramidal neurons and compared their firing latency following M1 stimuli to the latency of striatal synaptic responses. We found that the onset of M1-evoked synaptic responses in MSNs significantly preceded the firing of S1 neurons, demonstrating a direct synaptic excitation of MSNs by M1. However, the firing of MSNs seemed to require the combined excitatory effects of S1 and M1 CS inputs. This study directly demonstrates that the same somatosensory MSNs can process excitatory synaptic inputs from two functionally-related sensory and motor cortical regions converging into the same striatal sector. The effectiveness of these convergent cortical inputs in eliciting action potentials in MSNs may represent a key mechanism of striatum-related sensorimotor behaviors., Competing Interests: The authors have declared that no competing interests exist.

Objective: The neuronal underpinnings of impaired consciousness during absence seizures remain largely unknown. Spike-and-wave (SW) activity associated with absences imposes two extremely different states in cortical neurons, which transition from suprathreshold synaptic depolarizations during spike phases to membrane hyperpolarization and electrical silence during wave phases. To investigate whether this rhythmic alternation of neuronal states affects the processing of sensory information during seizures, we examined cortical and thalamic responsiveness to brief sensory stimuli in the different phases of the epileptic cycle., Methods: Electrocorticographic (ECoG) monitoring from the primary somatosensory cortex combined with intracellular recordings of subjacent pyramidal neurons, or extracellular recordings of somatosensory thalamic neurons, were performed in the Genetic Absence Epilepsy Rat From Strasbourg. Sensory stimuli consisted of pulses of compressed air applied to the contralateral whiskers., Results: Whisker stimuli delivered during spike phases evoked smaller depolarizing synaptic potentials and fewer action potentials in cortical neurons compared to stimuli occurring during wave phases. This spike-related attenuation of cortical responsiveness was accompanied by a reduced neuronal membrane resistance, likely due to the large increase in synaptic conductance. Sensory-evoked firing in thalamocortical neurons was also decreased during ECoG spikes as compared to wave phases, indicating that time-to-time changes in the thalamocortical volley may also contribute to the variability of cortical responses during seizures., Significance: These findings demonstrate that thalamocortical sensory processing during absence seizures is nonstationary and strongly suggest that the cortical impact of a given environmental stimulus is conditioned by its exact timing relative to the SW cycle. The lack of stability of thalamic and cortical responses along seizures may contribute to impaired conscious sensory perception during absences., (Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.)

We developed a new rodent model of reversible brain anoxia and performed continuous electrocorticographic (ECoG) and intracellular recordings of neocortical neurons to identify in real-time the cellular and network dynamics that successively emerge throughout the dying-to-recovery process. Along with a global decrease in ECoG amplitude, deprivation of oxygen supply resulted in an early surge of beta-gamma activities, accompanied by rhythmic membrane depolarizations and regular firing in pyramidal neurons. ECoG and intracellular signals were then dominated by low-frequency activities which progressively declined towards isoelectric levels. Cortical neurons during the isoelectric state underwent a massive membrane potential depolarizing shift, captured in the ECoG as a large amplitude triphasic wave known as the "wave-of-death" (WoD). This neuronal anoxic depolarization, associated with a block of action potentials and a loss of cell integrative properties, could however be reversed if brain re-oxygenation was rapidly restored (within 2-3.5 min). The subsequent slow repolarization of neocortical neurons resulted in a second identifiable ECoG wave we termed "wave-of-resuscitation" since it inaugurated the progressive regaining of pre-anoxic synaptic and firing activities. These results demonstrate that the WoD is not a biomarker of an irremediable death and unveil the cellular correlates of a novel ECoG wave that may be predictive of a successful recovery. The identification of real-time biomarkers of onset and termination of cell anoxic insult could benefit research on interventional strategies to optimize resuscitation procedures., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Absence Epilepsy (AE) is a prototypic epileptic syndrome that develops during brain maturation but cannot be fully explored in human patients. Genetic animal models, especially rats with spike-and-wave discharges recorded on the electroencephalogram, the hallmark of absence seizures, offer strong face validity with the human pathology that allows precise exploration of the pathophysiology of this form of epilepsy. Using an array of different methods, recent studies have demonstrated that spike-and-wave discharges are initiated in the primary somatosensory cortex and then rapidly propagate to motor cortices and thalamic nuclei. More specifically, in vivo electrophysiological intracellular recordings showed that the pyramidal neurons of the deep layers of this cortex exhibit fast activation, hyperexcitability and hypersynchronizing characteristics in favor of their role as ictogenic neurons in absence seizures. Furthermore, longitudinal studies during brain maturation suggest the progressive development of these features. Exploration of the different key players in the maturation of the primary somatosensory cortex should determine the anomalies that lead to the development of the cortical generator of absence seizures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Focal seizures are assumed to arise from a hypersynchronous activity affecting a circumscribed brain region. Using microelectrodes in seizure-generating deep mesial regions of 9 patients, we investigated the firing of hundreds of single neurons before, during, and after ictal electroencephalogram (EEG) discharges. Neuronal spiking activity at seizure initiation was highly heterogeneous and not hypersynchronous. Furthermore, groups of neurons showed significant changes in activity minutes before the seizure with no concomitant changes in the corresponding macroscopic EEG recordings. Altogether, our findings suggest that only limited subsets of neurons in epileptic depth regions initiate the seizure-onset and that ictogenic mechanisms operate in submillimeter-scale microdomains. Ann Neurol 2017 Ann Neurol 2017;82:1022-1028., (© 2017 American Neurological Association.)

A continuous isoelectric electroencephalogram reflects an interruption of endogenously-generated activity in cortical networks and systematically results in a complete dissolution of conscious processes. This electro-cerebral inactivity occurs during various brain disorders, including hypothermia, drug intoxication, long-lasting anoxia and brain trauma. It can also be induced in a therapeutic context, following the administration of high doses of barbiturate-derived compounds, to interrupt a hyper-refractory status epilepticus. Although altered sensory responses can be occasionally observed on an isoelectric electroencephalogram, the electrical membrane properties and synaptic responses of individual neurons during this cerebral state remain largely unknown. The aim of the present study was to characterize the intracellular correlates of a barbiturate-induced isoelectric electroencephalogram and to analyse the sensory-evoked synaptic responses that can emerge from a brain deprived of spontaneous electrical activity. We first examined the sensory responsiveness from patients suffering from intractable status epilepticus and treated by administration of thiopental. Multimodal sensory responses could be evoked on the flat electroencephalogram, including visually-evoked potentials that were significantly amplified and delayed, with a high trial-to-trial reproducibility compared to awake healthy subjects. Using an analogous pharmacological procedure to induce prolonged electro-cerebral inactivity in the rat, we could describe its cortical and subcortical intracellular counterparts. Neocortical, hippocampal and thalamo-cortical neurons were all silent during the isoelectric state and displayed a flat membrane potential significantly hyperpolarized compared with spontaneously active control states. Nonetheless, all recorded neurons could fire action potentials in response to intracellularly injected depolarizing current pulses and their specific intrinsic electrophysiological features were preserved. Manipulations of the membrane potential and intracellular injection of chloride in neocortical neurons failed to reveal an augmented synaptic inhibition during the isoelectric condition. Consistent with the sensory responses recorded from comatose patients, large and highly reproducible somatosensory-evoked potentials could be generated on the inactive electrocorticogram in rats. Intracellular recordings revealed that the underlying neocortical pyramidal cells responded to sensory stimuli by complex synaptic potentials able to trigger action potentials. As in patients, sensory responses in the isoelectric state were delayed compared to control responses and exhibited an elevated reliability during repeated stimuli. Our findings demonstrate that during prolonged isoelectric brain state neurons and synaptic networks are dormant rather than excessively inhibited, conserving their intrinsic properties and their ability to integrate and propagate environmental stimuli., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The epileptogenic processes leading to recurrent seizures in Genetic Epilepsies are largely unknown. Using the Genetic Absence Epilepsy Rat from Strasbourg, we investigated in vivo the network and single neuron mechanisms responsible for the early emergence of epileptic activity. Local field potential recordings in the primary somatosensory cortex (SoCx), from the second post-natal week to adulthood, showed that immature cortical discharges progressively evolved into typical spike-and-wave discharges following a 3-step maturation process. Intracellular recordings from deep-layer SoCx neurons revealed that this maturation was associated with an age-dependent increase in cortical neurons intrinsic excitability, combining a membrane depolarization and an enhancement of spontaneous firing rate with a leftward shift in their input-output relation. These cellular changes were accompanied by a progressive increase in the strength of the local synaptic activity associated with a growing propensity of neurons to generate synchronized oscillations. Chronic anti-absence treatment before the occurrence of mature cortical discharges did not alter epileptogenesis or the drug efficiency at adulthood. These findings demonstrate that recurrent absence seizures originate from the progressive acquisition of pro-ictogenic properties in SoCx neurons and networks during the post-natal period and that these processes cannot be interrupted by early anti-absence treatment., (© The Author 2017. Published by Oxford University Press.)

Gamma oscillations play a pivotal role in multiple cognitive functions. They enable coordinated activity and communication of local assemblies, while abnormalities in gamma oscillations exist in different neurological and psychiatric diseases. Thus, a specific rectification of gamma synchronization could potentially compensate the deficits in pathological conditions. Previous experiments have shown that animals can voluntarily modulate their gamma power through operant conditioning. Using a closed-loop experimental setup, we show in six intracerebrally recorded epileptic patients undergoing presurgical evaluation that intracerebral power spectrum can be increased in the gamma frequency range (30-80 Hz) at different fronto-temporal cortical sites in human subjects. Successful gamma training was accompanied by increased gamma power at other cortical locations and progressively enhanced cross-frequency coupling between gamma and slow oscillations (3-12 Hz). Finally, using microelectrode targets in two subjects, we report that upregulation of gamma activities is possible also in spatial micro-domains, without the spread to macroelectrodes. Overall, our findings indicate that intracerebral gamma modulation can be achieved rapidly, beyond the motor system and with high spatial specificity, when using micro targets. These results are especially significant because they pave the way for use of high-resolution therapeutic approaches for future clinical applications., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Key Points: Absence seizures are accompanied by spike-and-wave discharges in cortical electroencephalograms. These complex paroxysmal activities, affecting the thalamocortical networks, profoundly alter cognitive performances and preclude conscious perception. Here, using a well-recognized genetic model of absence epilepsy, we investigated in vivo how information processing was impaired in the ictogenic neurons, i.e. the population of cortical neurons responsible for seizure initiation. In between seizures, ictogenic neurons were more prone to generate bursting activity and their firing response to weak depolarizing events was considerably facilitated compared to control neurons. In the course of seizures, information processing became unstable in ictogenic cells, alternating between an increased and a decreased responsiveness to excitatory inputs, depending on the spike and wave patterns. The state-dependent modulation in the excitability of ictogenic neurons affects their inter-seizure transfer function and their time-to-time responsiveness to incoming inputs during absences., Abstract: Epileptic seizures result from aberrant cellular and/or synaptic properties that can alter the capacity of neurons to integrate and relay information. During absence seizures, spike-and-wave discharges (SWDs) interfere with incoming sensory inputs and preclude conscious experience. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established animal model of absence epilepsy, allows exploration of the cellular basis of this impaired information processing. Here, by combining in vivo electrocorticographic and intracellular recordings from GAERS and control animals, we investigated how the pro-ictogenic properties of seizure-initiating cortical neurons modify their integrative properties and input-output operation during inter-ictal periods and during the spike (S-) and wave (W-) cortical patterns alternating during seizures. In addition to a sustained depolarization and an excessive firing rate in between seizures, ictogenic neurons exhibited a pronounced hyperpolarization-activated depolarization compared to homotypic control neurons. Firing frequency versus injected current relations indicated an increased sensitivity of GAERS cells to weak excitatory inputs, without modifications in the trial-to-trial variability of current-induced firing. During SWDs, the W-component resulted in paradoxical effects in ictogenic neurons, associating an increased membrane input resistance with a reduction in the current-evoked firing responses. Conversely, the collapse of cell membrane resistance during the S-component was accompanied by an elevated current-evoked firing relative to W-sequences, which remained, however, lower compared to inter-ictal periods. These findings show a dynamic modulation of ictogenic neurons' intrinsic properties that may alter inter-seizure cortical function and participate in compromising information processing in cortical networks during absences., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Voluntary control of oscillatory activity represents a key target in the self-regulation of brain function. Using a real-time closed-loop paradigm and simultaneous macro- and micro-electrode recordings, we studied the effects of self-induced intracortical oscillatory activity (4-8 Hz) in seven neurosurgical patients. Subjects learned to robustly and specifically induce oscillations in the target frequency, confirmed by increased oscillatory event density. We have found that the session-to-session variability in performance was explained by the functional long-range decoupling of the target area suggesting a training-induced network reorganization. Downstream effects on more local activities included progressive cross-frequency-coupling with gamma oscillations (30-120 Hz), and the dynamic modulation of neuronal firing rates and spike timing, indicating an improved temporal coordination of local circuits. These findings suggest that effects of voluntary control of intracortical oscillations can be exploited to specifically target plasticity processes to reconfigure network activity, with a particular relevance for memory function or skill acquisition.

Unlabelled: Absence seizures are characterized by brief interruptions of conscious experience accompanied by oscillations of activity synchronized across many brain areas. Although the dynamics of the thalamocortical circuits are traditionally thought to underlie absence seizures, converging experimental evidence supports the key involvement of the basal ganglia (BG). In this theoretical work, we argue that the BG are essential for the maintenance of absence seizures. To this end, we combine analytical calculations with numerical simulations to investigate a computational model of the BG-thalamo-cortical network. We demonstrate that abnormally strong striatal feedforward inhibition can promote synchronous oscillatory activity that persists in the network over several tens of seconds as observed during seizures. We show that these maintained oscillations result from an interplay between the negative feedback through the cortico-subthalamo-nigral pathway and the striatal feedforward inhibition. The negative feedback promotes epileptic oscillations whereas the striatal feedforward inhibition suppresses the positive feedback provided by the cortico-striato-nigral pathway. Our theory is consistent with experimental evidence regarding the influence of BG on seizures (e.g., with the fact that a pharmacological blockade of the subthalamo-nigral pathway suppresses seizures). It also accounts for the observed strong suppression of the striatal output during seizures. Our theory predicts that well-timed transient excitatory inputs to the cortex advance the termination of absence seizures. In contrast with the thalamocortical theory, it also predicts that reducing the synaptic transmission along the cortico-subthalamo-nigral pathway while keeping constant the average firing rate of substantia nigra pars reticulata reduces the incidence of seizures., Significance Statement: Absence seizures are characterized by brief interruptions of consciousness accompanied by abnormal brain oscillations persisting tens of seconds. Thalamocortical circuits are traditionally thought to underlie absence seizures. However, recent experiments have highlighted the key role of the basal ganglia (BG). This work argues for a novel theory according to which the BG drive the oscillatory patterns of activity occurring during the seizures. It demonstrates that abnormally strong striatal feedforward inhibition promotes synchronous oscillatory activity in the BG-thalamo-cortical network and relate this property to the observed strong suppression of the striatal output during seizures. The theory is compatible with virtually all known experimental results, and it predicts that well-timed transient excitatory inputs to the cortex advance the termination of absence seizures., (Copyright © 2016 the authors 0270-6474/16/369618-15$15.00/0.)

DEP-domain containing 5 (DEPDC5), encoding a repressor of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies and focal cortical dysplasia. Here we established a global knockout rat using TALEN technology to investigate in vivo the impact of Depdc5-deficiency. Homozygous Depdc5(-/-) embryos died from embryonic day 14.5 due to a global growth delay. Constitutive mTORC1 hyperactivation was evidenced in the brains and in cultured fibroblasts of Depdc5(-/-) embryos, as reflected by enhanced phosphorylation of its downstream effectors S6K1 and rpS6. Consistently, prenatal treatment with mTORC1 inhibitor rapamycin rescued the phenotype of Depdc5(-/-) embryos. Heterozygous Depdc5(+/-) rats developed normally and exhibited no spontaneous electroclinical seizures, but had altered cortical neuron excitability and firing patterns. Depdc5(+/-) rats displayed cortical cytomegalic dysmorphic neurons and balloon-like cells strongly expressing phosphorylated rpS6, indicative of mTORC1 upregulation, and not observed after prenatal rapamycin treatment. These neuropathological abnormalities are reminiscent of the hallmark brain pathology of human focal cortical dysplasia. Altogether, Depdc5 knockout rats exhibit multiple features of rodent models of mTORopathies, and thus, stand as a relevant model to study their underlying pathogenic mechanisms., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The way neurons process information depends both on their intrinsic membrane properties and on the dynamics of the afferent synaptic network. In particular, endogenously-generated network activity, which strongly varies as a function of the state of vigilance, significantly modulates neuronal computation. To investigate how different spontaneous cerebral dynamics impact single neurons' integrative properties, we developed a new experimental strategy in the rat consisting in suppressing in vivo all cerebral activity by means of a systemic injection of a high dose of sodium pentobarbital. Cortical activities, continuously monitored by combined electrocorticogram (ECoG) and intracellular recordings are progressively slowed down, leading to a steady isoelectric profile. This extreme brain state, putting the rat into a deep comatose, was carefully monitored by measuring the physiological constants of the animal throughout the experiments. Intracellular recordings allowed us to characterize and compare the integrative properties of the same neuron embedded into physiologically relevant cortical dynamics, such as those encountered in the sleep-wake cycle, and when the brain was fully silent.

First characterized in 1982, the genetic absence epilepsy rat from Strasbourg (GAERS) has emerged as an animal model highly reminiscent of a specific form of idiopathic generalized epilepsy. Both its electrophysiological (spike-and-wave discharges) and behavioral (behavioral arrest) features fit well with those observed in human patients with typical absence epilepsy and required by clinicians for diagnostic purposes. In addition, its sensitivity to antiepileptic drugs closely matches what has been described in the clinic, making this model one of the most predictive. Here, we report how the GAERS, thanks to its spontaneous, highly recurrent and easily recognizable seizures on electroencephalographic recordings, allows to address several key-questions about the pathophysiology and genetics of absence epilepsy. In particular, it offers the unique possibility to explore simultaneously the neural circuits involved in the generation of seizures at different levels of integration, using multiscale methodologies, from intracellular recording to functional magnetic resonance imaging. In addition, it has recently allowed to perform proofs of concept for innovative therapeutic strategies such as responsive deep brain stimulation or synchrotron-generated irradiation based radiosurgery., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Transient high-frequency oscillations (HFOs; 150-600Hz) in local field potentials generated by human hippocampal and parahippocampal areas have been related to both physiological and pathological processes. The cellular basis and effects of normal and abnormal forms of HFOs have been controversial. This lack of agreement is clinically significant, because HFOs may be good markers of epileptogenic areas. Better defining the neuronal correlate of specific HFO frequency bands could improve electroencephalographic analyses made before epilepsy surgery., Methods: Here, we recorded HFOs in slices of the subiculum prepared from human hippocampal tissue resected for treatment of pharmacoresistant epilepsy. With combined intra- or juxtacellular and extracellular recordings, we examined the cellular correlates of interictal and ictal HFO events., Results: HFOs occurred spontaneously in extracellular field potentials during interictal discharges (IIDs) and also during pharmacologically induced preictal discharges (PIDs) preceding ictal-like events. Many of these events included frequencies >250Hz and so might be considered pathological, but a significant proportion were spectrally similar to physiological ripples (150-250Hz). We found that IID ripples were associated with rhythmic γ-aminobutyric acidergic and glutamatergic synaptic potentials with moderate neuronal firing. In contrast, PID ripples were associated with depolarizing synaptic inputs frequently reaching the threshold for bursting in most pyramidal cells., Interpretation: Our data suggest that IID and PID ripple-like oscillations (150-250Hz) in human epileptic hippocampus are associated with 2 distinct population activities that rely on different cellular and synaptic mechanisms. Thus, the ripple band could not help to disambiguate the underlying cellular processes., (© 2014 American Neurological Association.)

The amplitude and temporal dynamics of spontaneous synaptic activity in the cerebral cortex vary as a function of brain states. To directly assess the impact of different ongoing synaptic activities on neocortical function, we performed in vivo intracellular recordings from barrel cortex neurons in rats under two pharmacological conditions generating either oscillatory or tonic synaptic drive. Cortical neurons membrane excitability and firing responses were compared, in the same neurons, before and after complete suppression of background synaptic drive following systemic injection of a high dose of anaesthetic. Compared to the oscillatory state, the tonic pattern resulted in a more depolarized and less fluctuating membrane potential (Vm), a lower input resistance (Rm) and steeper relations of firing frequency versus injected current (F-I). Whatever their temporal dynamics, suppression of background synaptic activities increased mean Vm, without affecting Rm, and induced a rightward shift of F-I curves. Both types of synaptic drive generated a high variability in current-induced firing rate and patterns in cortical neurons, which was much reduced after removal of spontaneous activity. These findings suggest that oscillatory and tonic synaptic patterns differentially facilitate the input-output function of cortical neurons but result in a similar moment-to-moment variability in spike responses to incoming depolarizing inputs., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Recent evidence suggests that some seizures are preceded by preictal changes that start from minutes to hours before an ictal event. Nevertheless an adequate statistical evaluation in a large database of continuous multiday recordings is still missing. Here, we investigated the existence of preictal changes in long-term intracranial recordings from 53 patients with intractable partial epilepsy (in total 531 days and 558 clinical seizures). We describe a measure of brain excitability based on the slow modulation of high-frequency gamma activities (40-140 Hz) in ensembles of intracranial contacts. In prospective tests, we found that this index identified preictal changes at levels above chance in 13.2% of the patients (7/53), suggesting that results may be significant for the whole group (p < 0.05). These results provide a demonstration that preictal states can be detected prospectively from EEG data. They advance understanding of the network dynamics leading to seizure and may help develop novel seizure prediction algorithms.

Radiotherapy has shown some efficacy for epilepsies but the insufficient confinement of the radiation dose to the pathological target reduces its indications. Synchrotron-generated X-rays overcome this limitation and allow the delivery of focalized radiation doses to discrete brain volumes via interlaced arrays of microbeams (IntMRT). Here, we used IntMRT to target brain structures involved in seizure generation in a rat model of absence epilepsy (GAERS). We addressed the issue of whether and how synchrotron radiotherapeutic treatment suppresses epileptic activities in neuronal networks. IntMRT was used to target the somatosensory cortex (S1Cx), a region involved in seizure generation in the GAERS. The antiepileptic mechanisms were investigated by recording multisite local-field potentials and the intracellular activity of irradiated S1Cx pyramidal neurons in vivo. MRI and histopathological images displayed precise and sharp dose deposition and revealed no impairment of surrounding tissues. Local-field potentials from behaving animals demonstrated a quasi-total abolition of epileptiform activities within the target. The irradiated S1Cx was unable to initiate seizures, whereas neighboring non-irradiated cortical and thalamic regions could still produce pathological oscillations. In vivo intracellular recordings showed that irradiated pyramidal neurons were strongly hyperpolarized and displayed a decreased excitability and a reduction of spontaneous synaptic activities. These functional alterations explain the suppression of large-scale synchronization within irradiated cortical networks. Our work provides the first post-irradiation electrophysiological recordings of individual neurons. Altogether, our data are a critical step towards understanding how X-ray radiation impacts neuronal physiology and epileptogenic processes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Absence seizures are caused by brief periods of abnormal synchronized oscillations in the thalamocortical loops, resulting in widespread spike-and-wave discharges (SWDs) in the electroencephalogram (EEG). SWDs are concomitant with a complete or partial impairment of consciousness, notably expressed by an interruption of ongoing behaviour together with a lack of conscious perception of external stimuli. It is largely considered that the paroxysmal synchronizations during the epileptic episode transiently render the thalamocortical system incapable of transmitting primary sensory information to the cortex. Here, we examined in young patients and in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established genetic model of absence epilepsy, how sensory inputs are processed in the related cortical areas during SWDs. In epileptic patients, visual event-related potentials (ERPs) were still present in the occipital EEG when the stimuli were delivered during seizures, with a significant increase in amplitude compared to interictal periods and a decrease in latency compared to that measured from non-epileptic subjects. Using simultaneous in vivo EEG and intracellular recordings from the primary somatosensory cortex of GAERS and non-epileptic rats, we found that ERPs and firing responses of related pyramidal neurons to whisker deflection were not significantly modified during SWDs. However, the intracellular subthreshold synaptic responses in somatosensory cortical neurons during seizures had larger amplitude compared to quiescent situations. These convergent findings from human patients and a rodent genetic model show the persistence of cortical responses to sensory stimulations during SWDs, indicating that the brain can still process external stimuli during absence seizures. They also demonstrate that the disruption of conscious perception during absences is not due to an obliteration of information transfer in the thalamocortical system. The possible mechanisms rendering the cortical operation ineffective for conscious perception are discussed, but their definite elucidation will require further investigations.

Responsiveness of cortical neurons to sensory inputs can be altered by experience and learning. While synaptic plasticity is generally proposed as the underlying cellular mechanism, possible contributions of activity-dependent changes in intrinsic excitability remain poorly investigated. Here, we show that periods of rhythmic firing in rat barrel cortex layer 5 pyramidal neurons can trigger a long-lasting increase or decrease in their membrane excitability in vivo. Potentiation of cortical excitability consisted of an increased firing in response to intracellular stimulation and a reduction in threshold current for spike initiation. Conversely, depression of cortical excitability was evidenced by an augmented firing threshold leading to a reduced current-evoked spiking. The direction of plasticity depended on the baseline level of spontaneous firing rate and cell excitability. We also found that changes in intrinsic excitability were accompanied by corresponding modifications in the effectiveness of sensory inputs. Potentiation and depression of cortical neuron excitability resulted, respectively, in an increased or decreased firing probability on whisker-evoked synaptic responses, without modifications in the synaptic strength itself. These data suggest that bidirectional intrinsic plasticity could play an important role in experience-dependent refinement of sensory cortical networks.

Electroclinical investigations in human patients and experimental studies from genetic models demonstrated that spike-and-wave discharges (SWDs) associated with absence seizures have a cortical onset. In the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), SWDs are initiated by the paroxysmal discharges of ictogenic pyramidal neurones located in the deep layers of the somatosensory cortex. However, the cellular and synaptic mechanisms that control the ictal discharges of seizure-initiating neurones remain unclear. Here, by the means of in vivo paired electroencephalographic (EEG) and intracellular recordings in the GAERS cortical focus, we explored the participation of the intracortical inhibitory system in the control of paroxysmal activities in ictogenic neurones. We found that their firing during EEG paroxysms was interrupted by the occurrence of hyperpolarizing synaptic events that reversed in polarity below action potential threshold. Intracellular injection of Cl(-) dramatically increased the amplitude of the paroxysmal depolarizations and the number of generated action potentials, strongly suggesting that the inhibitory synaptic potentials were mediated by GABA(A) receptors. Consistently, we showed that intracellularly recorded GABAergic interneurones fired, during seizures, shortly after (∼+8 ms) the discharge of ictogenic neurones and displayed a rhythmic bursting that coincided with the inhibitory synaptic events in neighbouring pyramidal ictogenic cells. In contrast with other forms of epilepsy, our findings suggest that paroxysmal activities in the cortical pyramidal cells initiating absence seizures are negatively controlled by a feedback Cl(-)-mediated inhibition likely resulting from the fast recurrent activation of intracortical GABAergic interneurones by the ictogenic cells themselves., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

The dorsolateral striatum is critically involved in the execution and learning of sensorimotor tasks. It is proposed that this striatal function is achieved by the integration of convergent somatosensory and motor corticostriatal (CS) inputs in striatal medium-spiny neurons (MSNs). However, the cellular mechanisms of integration and propagation of somatosensory information in the CS pathway remain unknown. Here, by means of in vivo intracellular recordings in the rat, we analysed how sensory events generated by multi-whisker deflection, which provide essential somaesthetic information in rodents, are processed in contralateral barrel cortex layer 5 neurons and in the related somatosensory striatal MSNs. Pyramidal layer 5 barrel cortex neurons, including neurons antidromically identified as CS, responded to whisker deflection by depolarizing post-synaptic potentials that could reliably generate action potential discharge. In contrast, only half of recorded somatosensory striatal MSNs displayed whisker-evoked synaptic depolarizations that were effective in eliciting action potentials in one-third of responding neurons. The remaining population of MSNs did not exhibit any detectable electrical events in response to whisker stimulation. The relative inconstancy of sensory-evoked responses in MSNs was due, at least in part, to a Cl(-)-dependent membrane conductance concomitant with the cortical inputs,which was probably caused by whisker-induced activation of striatal GABAergic interneurons. Our results suggest that the propagation of whisker-mediated sensory flow through the CS pathway results in a refinement of sensory information in the striatum, which might allow the selection of specific sets of MSNs that are functionally significant during a given somaesthetic-guided behaviour.

Mesial temporal lobe epilepsy (MTLE) is characterized by focal seizures, associated with hippocampal sclerosis, and often resistance to antiepileptic drugs. The parafascicular nucleus (PF) of the thalamus is involved in the generation of physiological oscillatory rhythms. It receives excitatory inputs from the cortex and inhibitory inputs from the basal ganglia, a system implicated in the control of epileptic seizures. The aim of this study was to examine the involvement of the PF in the occurrence of hippocampal paroxysmal discharges (HPDs) in a chronic animal model of MTLE in male mice. We recorded the local field potential (LFP) and the extracellular and intracellular activity of hippocampal and PF neurons during spontaneous HPDs in vivo. The end of the HPDs was concomitant with a slow repolarization in hippocampal neurons leading to an electrical silence. In contrast, it was associated in the PF with a transient increase in the power of the 10-20 Hz band in LFPs and a depolarization of PF neurons resulting in a sustained firing. We tested the role of the PF in the control of HPDs by single 130 Hz electrical stimulation of this nucleus and bilateral intra-PF injection of NMDA and GABA(A) antagonist and agonist. High-frequency PF stimulation interrupted ongoing HPDs at an intensity devoid of behavioral effects. NMDA antagonist and GABA(A) agonist suppressed hippocampal discharges in a dose-dependent way, whereas NMDA agonist and GABA(A) antagonist increased HPDs. Altogether, these data suggest that the PF nucleus plays a role in the modulation of MTLE seizures.

Absence seizures consist of bilateral spike-and-wave discharges (SWDs) occurring over widespread cortical and thalamic regions. In genetic models of absence epilepsy, recent in vivo investigations indicate that SWDs emerge first in the facial somatosensory cortex and then propagate via the corticothalamocortical loop. The specific involvement of this cortical region in ictogenic processes remained to be established and the participation of its related thalamocortical system in seizure initiation remained unclear. Here, using electrocorticographic (ECoG) and intracellular recordings in vivo from cortex and thalamus in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), we obtained novel evidence for the cortical focus theory of absence epilepsy. We report that blockade of action potential discharge and synaptic activities in facial somatosensory cortical neurons, by topical application of tetrodotoxin, prevents the occurrence of paroxysmal activities in local and distant cortical neurons and ECoGs, as well as in thalamocortical neurons in register with the somatosensory cortex. In contrast, pharmacological inhibition of a remote motor cortical region or of the related thalamic nuclei did not suppress ictal activities in the somatosensory cortex. This study demonstrates that SWDs in GAERS have a focal origin within the facial somatosensory cortex, which is sufficient and necessary to generate ictal activities.

Synaptic plasticity is classically considered as the neuronal substrate for learning and memory. However, activity-dependent changes in neuronal intrinsic excitability have been reported in several learning-related brain regions, suggesting that intrinsic plasticity could also participate to information storage. Compared to synaptic plasticity, there has been little exploration of the properties of induction and expression of intrinsic plasticity in an intact brain. Here, by the means of in vivo intracellular recordings in the rat we have examined how the intrinsic excitability of layer V motor cortex pyramidal neurones is altered following brief periods of repeated firing. Changes in membrane excitability were assessed by modifications in the discharge frequency versus injected current (F-I) curves. Most (approximately 64%) conditioned neurones exhibited a long-lasting intrinsic plasticity, which was expressed either by selective changes in the current threshold or in the slope of the F-I curve, or by concomitant changes in both parameters. These modifications in the neuronal input-output relationship led to a global increase or decrease in intrinsic excitability. Passive electrical membrane properties were unaffected by the intracellular conditioning, indicating that intrinsic plasticity resulted from modifications of voltage-gated ion channels. These results demonstrate that neocortical pyramidal neurones can express in vivo a bidirectional use-dependent intrinsic plasticity, modifying their sensitivity to weak inputs and/or the gain of their input-output function. These multiple forms of experience-dependent intrinsic changes, which expand the computational abilities of individual neurones, could shape new network dynamics and thus might participate in the formation of mnemonic motor engrams.

Absence epilepsy is a form of generalized epilepsy commonly seen in children. The neuronal process by which ethosuximide (ETX), a first choice anti-absence drug, prevents absence seizures is still unresolved. Recent clinical findings have indicated that focal cortical regions are involved during absence seizures. Consistently, it has been shown in genetic models of absence epilepsy that epileptic discharges arise from a delimited region of the cerebral cortex. Here, we made simultaneous in vivo electrocorticographic and intracellular recordings from the cortical focus of the genetic absence epilepsy rat from Strasbourg and examined the effects of systemic injection of ETX at a therapeutic concentration. We show that the interruption of seizures by ETX is correlated with a recovery, in the hyperactive focus neurons, of physiologic values of membrane potential, firing rate, and pattern, as measured in analogous neurons from nonepileptic rats. These data suggest that the anti-absence action of ETX results from the conversion of ictogenic cortical neurons into normal cortical neurons.

Typical absence has long been considered as the prototypic form of generalized nonconvulsive epileptic seizures. Recent investigations in patients and animal models suggest that absence seizures could originate from restricted regions of the cerebral cortex. However, the cellular and local network processes of seizure initiation remain unknown. Here, we show that absence seizures in Genetic Absence Epilepsy Rats from Strasbourg, a well established genetic model of this disease, arise from the facial somatosensory cortex. Using in vivo intracellular recordings, we found that epileptic discharges are initiated in layer 5/6 neurons of this cortical region. These neurons, which show a distinctive hyperactivity associated with a membrane depolarization, lead the firing of distant cortical cells during the epileptic discharge. Consistent with their ictogenic properties, neurons from this "focus" exhibit interictal and preictal oscillations that are converted into epileptic pattern. These results confirm and extend the "focal hypothesis" of absence epilepsy and provide a cellular scenario for the initiation and generalization of absence seizures.

Absence seizures are characterized by bilaterally synchronous spike-and-wave discharges (SWDs) in the electroencephalogram, which reflect abnormal oscillations in corticothalamic networks. Although it was suggested that basal ganglia could modulate, via their feedback circuits to the cerebral cortex, the occurrence of SWDs, the cellular and network mechanisms underlying such a subcortical control of absence seizures remain unknown. The GABAergic projections from substantia nigra pars reticulata (SNR) to thalamocortical neurons of the ventral medial (VM) thalamic nucleus provide a potent network for the control of absence seizures by basal ganglia. The present in vivo study provides the first description of the activity of VM thalamic neurons during seizures in the genetic absence epilepsy rats from Strasbourg, a well established model of absence epilepsy. Cortical paroxysms were accompanied in VM thalamic neurons by rhythmic bursts of action potentials. Pharmacological blockade of excitatory inputs of nigrothalamic neurons led to a transient interruption of SWDs, correlated with a change in the activity of thalamic cells, which was increased in frequency and converted into a sustained arrhythmic firing pattern. Simultaneously, cortical neurons exhibited a decrease in their firing rate that was associated with an increase in membrane polarization and a decrease in input resistance. These new findings demonstrate that an inhibition of SNR neurons changes the activity of their thalamic targets, which in turn could affect cortical neurons excitability and, consequently, the generation of cortical epileptic discharges. Thus, the nigro-thalamo-cortical pathway may provide an on-line system control of absence seizures.

Together with the internal segment of the globus pallidus (GP(i)), the pars reticulata of the substantia nigra (SNr) provides a main output nucleus of the basal ganglia (BG) where the final stage of information processing within this system takes place. In the last decade, progress on the anatomical organization and functional properties of BG output neurons have shed some light on the mechanisms of integration taking place in these nuclei and leading to normal and pathological BG outflow. In this review focused on the SNr, after describing how the anatomical arrangement of nigral cells and their afferents determines specific input-output registers, we examine how the basic electrophysiological properties of the cells and their interaction with synaptic inputs contribute to the spatio-temporal shaping of BG output. The reported data show that the intrinsic membrane properties of the neurons subserves a tonic discharge allowing BG to gate the transmission of information to motor and cognitive systems thereby contributing to appropriate selection of behavior.

Striatal medium-sized spiny neurons (MSNs) integrate and convey information from the cerebral cortex to the output nuclei of the basal ganglia. Intracellular recordings from anesthetized animals show that MSNs undergo spontaneous transitions between hyperpolarized and depolarized states. State transitions, regarded as necessary for eliciting action potential firing in MSNs, are thought to control basal ganglia function by shaping striatal output. Here, we use an anesthetic-free rat preparation to show that the intracellular activity of MSNs is not stereotyped and depends critically on vigilance state. During slow-wave sleep, much as during anesthesia, MSNs displayed rhythmic step-like membrane potential shifts, correlated with cortical field potentials. However, wakefulness was associated with a completely different pattern of temporally disorganized depolarizing synaptic events of variable amplitude. Transitions from slow-wave sleep to wakefulness converted striatal discharge from a cyclic brisk firing to an irregular pattern of action potentials. These findings illuminate different capabilities of information processing in basal ganglia networks, suggesting in particular that a novel style of striatal computation is associated with the waking state.

Spontaneous high-voltage rhythmic spike (HVRS) discharges at 6-12 Hz have been widely described in the electrocorticogram (EcoG) of Long-Evans rats. These ECoG oscillations have been proposed to reflect a state of attentive immobility allowing the optimization of sensory integration within the corticothalamic pathway. This hypothesis has been challenged by recent studies emphasizing similarities between HVRS discharges and spike-and-wave discharges (SWDs) in well-established rat genetic models of absence epilepsy. Here, we made in vivo intracellular recordings to determine, for the first time, the cellular mechanisms responsible for the synchronized oscillations in the corticothalamic loop during HVRS discharges in the Long-Evans rats. We show that HVRS discharges are associated in corticothalamic neurones with rhythmic suprathreshold synaptic depolarizations superimposed on a tonic hyperpolarization, likely due to a process of synaptic disfacilitation. Simultaneously, thalamocortical neurones exhibit a large-amplitude 'croissant'-shaped membrane hyperpolarization with a voltage sensitivity suggesting a potassium-dependent mechanism. This thalamic hyperpolarizing envelope was associated with a membrane oscillation resulting from interactions between excitatory synaptic inputs, a chloride-dependent inhibitory conductance and voltage-gated intrinsic currents. These cortical and thalamic cellular mechanisms underlying HVRS activity in Long-Evans rats are remarkably similar to those previously described in the thalamocortical networks during SWDs. Thus, the present study provides an additional support to the hypothesis that HVRS activity in Long-Evans rats is an absence-like seizure activity.

Discharge activities and local field potentials were recorded in the orofacial motor cortex and in the corresponding rostrolateral striatum of urethane-anesthetized rats. Striatal projection neurons were identified by antidromic activation and fast-spiking GABAergic interneurons (FSIs) by their unique characteristics: briefer spike and burst responses. Juxtacellular injection of neurobiotin combined with parvalbumin immunohistochemistry validated this identification. Spontaneous activities and spike responses to cortical stimulation were recorded during both states of cortical activity: slow waves and desynchronization. Both FSI and projection neurons spontaneously discharged synchronously with slow waves at the maximum of cortical activity, but, on average, FSIs were much more active. Cortical desynchronization enhanced FSI activity and facilitated their spike responses to cortical stimulation, whereas opposite effects were observed regarding projection neurons. Experimental conditions favoring FSI discharge were always associated with a decrease in the firing activity of projection neurons. Spike responses to cortical stimulation occurred earlier (latency difference, 4.6 ms) and with a lower stimulation current for FSIs than for projection neurons. Moreover, blocking GABA(A) receptors by local picrotoxin injection enhanced the spike response of projection neurons, and this increase was larger in experimental conditions favoring FSI responses. Therefore, on average, FSIs exert in vivo a powerful feedforward inhibition on projection neurons. However, a few projection neurons were actually more sensitive to cortical stimulation than FSIs. Moreover, picrotoxin, which revealed FSI inhibition, preferentially affected projection neurons exhibiting the weakest sensitivity to cortical stimulation. Thus, feedforward inhibition by FSIs filters cortical information effectively transmitted by striatal projection neurons.

Absence seizures are characterized by impairment of consciousness associated with bilaterally synchronous spike-and-wave discharges (SWDs) in the electroencephalogram (EEG), which reflect paroxysmal oscillations in thalamocortical networks. Although recent studies suggest that the subthalamic nucleus (STN) provides an endogenous control system that influences the occurrence of absence seizures, the mechanisms of propagation of cortical epileptic discharges in the STN have never been explored. The present study provides the first description of the electrophysiological activity in the cortico-subthalamo-pallidal network during absence seizures in the genetic absence epilepsy rats from Strasbourg, a well established model of absence epilepsy. In corticosubthalamic neurons, the SWDs were associated with repetitive suprathreshold depolarizations correlated with EEG spikes. These cortical paroxysms were reflected in the STN by synchronized, rhythmic, high-frequency bursts of action potentials. Intracellular recordings revealed that the intraburst pattern in STN neurons was sculpted by an early depolarizing synaptic potential, followed by a short hyperpolarization and a rebound of excitation. The rhythmic hyperpolarizations in STN neurons during SWDs likely originate from a subpopulation of pallidal neurons exhibiting rhythmic bursting temporally correlated with the EEG spikes. The repetitive discharges in STN neurons accompanying absence seizures might convey powerful excitation to basal ganglia output nuclei and, consequently, may participate in the control of thalamocortical SWDs.

Experience-dependent changes in corticostriatal transmission efficacy are likely to support the role of the striatum in reinforcement-based motor learning. Whereas long-term depression at glutamatergic corticostriatal synapses has long been regarded as the normal form of striatal plasticity, recent work provides evidence that use-dependent potentiation can naturally occur at these connections through an increase in both synaptic efficacy and postsynaptic intrinsic excitability. By decreasing the weight of cortical inputs required to fire striatal output neurons, short-term and long-term potentiation at corticostriatal connections can jointly participate in the formation of sensorimotor links by which specific context-dependent patterns of cortical activity can engage selected motor programs.

Absence seizures are characterized by impairment of consciousness associated with widespread bilaterally synchronous spike-and-wave discharges (SWDs) in the electroencephalogram (EEG), which reflect highly synchronized oscillations in thalamocortical networks. Although recent pharmacological studies suggest that the basal ganglia could provide a remote control system for absence seizures, the mechanisms of propagation of epileptic discharges in these subcortical nuclei remain unknown. In the present study, we provide the first description of the electrical events in the corticostriatal pathway during spontaneous SWDs in the genetic absence epilepsy rats from Strasbourg (GAERS), a genetic model of absence epilepsy. In corticostriatal neurons, the SWDs were associated with suprathreshold rhythmic depolarizations in-phase with local EEG spikes. Consistent with this synchronized firing in their excitatory cortical afferents, striatal output neurons (SONs) exhibited, during SWDs, large-amplitude rhythmic synaptic depolarizations. However, SONs did not discharge during SWDs. Instead, the rhythmic synaptic excitation of SONs was shunted by a Cl(-)-dependent increase in membrane conductance that was temporally correlated with bursts of action potentials in striatal GABAergic interneurons. The reduced SON excitability accompanying absence seizures may participate in the control of SWDs by affecting the flow of cortical information within the basal ganglia circuits.

The collision of pre- and postsynaptic activity is known to provide a trigger for controlling the gain of synaptic transmission between neurons. Here, using in vivo intracellular recordings of rat striatal output neurons, we analyse the effect of a single action potential, generated by ongoing synaptic activity, on subsequent excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the cerebral cortex. This pairing induced a short-term increase in the probability that cortically evoked EPSPs caused striatal cells to fire. This enhanced EPSP-spike coupling was associated with a decrease in the voltage firing threshold with no apparent change in the synaptic strength itself. Antidromic action potentials in striatal cells were also able to induce the facilitation while subthreshold EPSPs were ineffective, indicating that the postsynaptic spike was necessary and sufficient for the induction of the plasticity. A prior spontaneous action potential also enhanced the probability with which directly applied current pulses elicited firing, suggesting that the facilitation originated from changes in the intrinsic electrical properties of the postsynaptic cell. Using whole-cell recordings in cortico-striatal slices, we found that the increase in membrane excitability as well as in EPSP-spike coupling was abolished by low concentration of 4-aminopyridine. This suggests that the intrinsic plasticity results from a time-dependent modulation of a striatal voltage-dependent potassium current available close to the firing threshold. Action potentials thus provide a postsynaptic signal, not only for associative synaptic plasticity but also for activity-dependent intrinsic plasticity, which directly controls the efficacy of coupling between pre- and postsynaptic neurons.

It is commonly assumed that spontaneous activity of striatal output neurons is characterized by a two-state behavior. This assumption is mainly based on in vivo intracellular recordings under urethane and/or ketamine-xylazine anesthesia showing that striatal neurons oscillate between two preferred membrane potentials, a Down state (hyperpolarized level), resulting from an inwardly rectifying potassium conductance, and an Up state (depolarized level) caused by complex interactions between a barrage of cortical synaptic excitation and voltage-dependent potassium conductances. However, a recent comparative study using different anesthetics showed that striatal neurons can exhibit various shapes of synaptic activity depending on the temporal structure and the degree of synchronization of their cortico-striatal afferents. These new data demonstrate that the "classical" Up and Down states do not provide the unique spontaneous activity that can be encountered in striatal neurons in vivo. Rather we propose that striatal neurons should exhibit various synaptic activities and firing patterns depending on the states of vigilance. This hypothesis would be validated in further experiments in which the intracellular activity of striatal neurons will be recorded during the natural sleep-wake cycle.

The substantia nigra pars reticulata (SNR) constitutes a major output nucleus of the basal ganglia where the final stage of information processing within this system takes place. In this study, using juxtacellular labeling and three-dimensional reconstruction methods, we investigated the spatial organization of the intranigral innervation provided by single GABAergic projection neurons from the sensory-motor subdivision of the rat SNR. Confirming previous observations, most labeled SNR cells were found to possess a local axonal network innervating the pars reticulata and pars compacta (SNC). Within the SNR, axons of these cells were distributed along curved laminas enveloping a dorsolaterally located core, thus mostly respecting the onion-like compartmentalization of this nucleus. Although the axonal projection field mostly remained confined to the dendritic field of the parent neuron, it usually extended beyond its limits in caudal, lateral, and/or dorsal directions. Because SNR cells are GABAergic, this pattern of axonal projection suggests the existence of lateral inhibitory interactions between neurons belonging to the same as well as to adjacent functional subdivisions. Axonal projections of SNR cells to the SNC formed longitudinal bands. These bands partly occupied the SNC region projecting to the striatal sector from which parent SNR cells receive their afferents. These data indicate that SNR cells contribute to an indirect nigrostriatal loop circuit through which the striatum could upregulate its level of dopaminergic transmission via a disinhibition of nigrostriatal neurons. Spatial relationships between elements of this indirect nigrostriatonigral circuit indicate that this circuit operates in both a closed and open loop manner.

The basal ganglia are composed of a set of forebrain structures implicated in the adaptive control of behaviour. These structures process information originating from the entire cerebral cortex, as well as from nonspecific thalamic nuclei and the amygdala. In turn, they redistribute the integrated signals toward thalamic and brainstem nuclei related to motor, premotor, prefrontal and limbic cortical areas. During the two last decades, there has been increasing experimental evidence that the basal ganglia circuitry may be part of a remote control system influencing the spread of epileptic seizures. In the present article, we review the basic principles of the functional organization of the basal ganglia and provide experimental data on the activity that is transmitted by the cerebral cortex to the input stage of the basal ganglia during absence seizures. The functional organization of the basal ganglia supports the current hypothesis that these structures can dynamically control generalized seizures through their input-output relationships.

This study reports the first intracellular recordings obtained during spontaneous, genetically determined spike and wave discharges (SWDs) in nucleus reticularis thalami (NRT) neurons from the genetic absence epilepsy rats from Strasbourg (GAERS), a model that closely reproduces the typical features of childhood absence seizures. A SWD started with a large hyperpolarization, which was independent of the preceding firing, and decreased in amplitude but did not reverse in polarity up to potentials >/= -90 mV. This hyperpolarization and the slowly decaying depolarization that terminated a SWD were unaffected by recording with KCl-filled electrodes. The prolonged (up to 15 action potentials), high-frequency bursts present during SWDs were tightly synchronized between adjacent neurons, correlated with the EEG spike component, and generated by a low-threshold Ca(2+) potential, which, in turn, was brought about by the summation of high-frequency, small-amplitude depolarizing potentials. Fast hyperpolarizing IPSPs were not detected either during or in the absence of SWDs. Recordings with KCl-filled electrodes, however, showed a more depolarized resting membrane potential and a higher background firing, whereas the SWD-associated bursts had a longer latency to the EEG spike and a lower intraburst frequency. This novel finding demonstrates that spontaneous genetically determined SWDs occur in the presence of intra-NRT lateral inhibition. The unmasking of these properties in the GAERS NRT confirms their unique association with spontaneous genetically determined SWDs and thus their likely involvement in the pathophysiological processes of the human condition.