Sleep waves in a large-scale corticothalamic model constrained by activities intrinsic to neocortical networks and single thalamic neurons.

AIM: Many biophysical and non-biophysical models have been able to reproduce the corticothalamic activities underlying different EEG sleep rhythms but none of them included the known ability of neocortical networks and single thalamic neurons to generate some of these waves intrinsically. METHODS: We built a large-scale corticothalamic model with a high fidelity in anatomical connectivity consisting of a single cortical column and first- and higher-order thalamic nuclei. The model is constrained by different neocortical excitatory and inhibitory neuronal populations eliciting slow (<1 Hz) oscillations and by thalamic neurons generating sleep waves when isolated from the neocortex. RESULTS: Our model faithfully reproduces all EEG sleep waves and the transition from a desynchronized EEG to spindles, slow (<1 Hz) oscillations, and delta waves by progressively increasing neuronal membrane hyperpolarization as it occurs in the intact brain. Moreover, our model shows that slow (<1 Hz) waves most often start in a small assembly of thalamocortical neurons though they can also originate in cortical layer 5. Moreover, the input of thalamocortical neurons increases the frequency of EEG slow (<1 Hz) waves compared to those generated by isolated cortical networks. CONCLUSION: Our simulations challenge current mechanistic understanding of the temporal dynamics of sleep wave generation and suggest testable predictions.

Spike-and-wave discharges of absence seizures in a sleep waves-constrained corticothalamic model.

AIMS: Recurrent network activity in corticothalamic circuits generates physiological and pathological EEG waves. Many computer models have simulated spike-and-wave discharges (SWDs), the EEG hallmark of absence seizures (ASs). However, these models either provided detailed simulated activity only in a selected territory (i.e., cortical or thalamic) or did not test whether their corticothalamic networks could reproduce the physiological activities that are generated by these circuits. METHODS: Using a biophysical large-scale corticothalamic model that reproduces the full extent of EEG sleep waves, including sleep spindles, delta, and slow (<1 Hz) waves, here we investigated how single abnormalities in voltage- or transmitter-gated channels in the neocortex or thalamus led to SWDs. RESULTS: We found that a selective increase in the tonic γ-aminobutyric acid type A receptor (GABA-A) inhibition of first-order thalamocortical (TC) neurons or a selective decrease in cortical phasic GABA-A inhibition is sufficient to generate ~4 Hz SWDs (as in humans) that invariably start in neocortical territories. Decreasing the leak conductance of higher-order TC neurons leads to ~7 Hz SWDs (as in rodent models) while maintaining sleep spindles at 7-14 Hz. CONCLUSION: By challenging key features of current mechanistic views, this simulated ictal corticothalamic activity provides novel understanding of ASs and makes key testable predictions.

A quantitative and T-pattern analysis of anxiety-like behavior in male GAERS, NEC, and Wistar rats bred under the same conditions, against a commercially available Wistar control group in the hole board and elevated plus maze tests.

AIM: The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbred polygenic model of childhood absence epilepsy (CAE), which, as their non-epileptic control (NEC) rats, are derived from Wistar rats. While the validity of GAERS in reproducing absence seizures is well established, its use as a model for CAE psychiatric comorbidities has been subject to conflicting findings. Differences in colonies, experimental procedures, and the use of diverse controls from different breeders may account for these disparities. Therefore, in this study, we compared GAERS, NEC, and Wistar bred in the same animal facility with commercially available Wistar (Cm Wistar) as a third control. METHODS: We performed hole board (HB) and elevated plus maze (EPM) tests that were analyzed with standard quantitative and T-pattern analysis in male, age-matched Cm Wistar and GAERS, NEC, and Wistar, bred under the same conditions, to rule out the influence of different housing factors and provide extra information on the structure of anxiety-like behavior of GAERS rats. RESULTS: Quantitative analysis showed that GAERS and NEC had similar low anxiety-like behavior when compared to Cm Wistar but not to Wistar rats, although a higher hole-focused exploration was revealed in NEC. T-pattern analysis showed that GAERS, NEC, and Wistar had a similar anxiety status, whereas GAERS and NEC exhibited major differences with Cm Wistar but not Wistar rats. EPM results indicated that GAERS and NEC also have similar low anxiety compared to Cm Wistar and/or Wistar rats. Nevertheless, the analysis of the T-pattern containing open-arm entry showed GAERS and Wistar to be less anxious than NEC and Cm Wistar rats. CONCLUSION: To summarize, comorbid anxiety may not be present in male GAERS rats. This study also highlighted the importance of including a control Wistar group bred under the same conditions when evaluating their behavior, as using Wistar rats from commercial breeders can lead to misleading results.

Cognitive comorbidities of experimental absence seizures are independent of anxiety.

Typical absence seizures (ASs) are brief periods of lack of consciousness, associated with 2.5-4 Hz spike-wave discharges (SWDs) in the EEG, which are highly prevalent in children and teenagers. The majority of probands in these young epileptic cohorts show neuropsychological comorbidities, including cognitive, memory and mood impairments, even after the seizures are pharmacologically controlled. Similar cognition and memory deficits have been reported in different, but not all, genetic animal models of ASs. However, since these impairments are subtle and highly task-specific their presence may be confounded by an anxiety-like phenotype and no study has tested anxiety and memory in the same animals. Moreover, the majority of studies used non-epileptic inbred animals as the only control strain and this may have contributed to a misinterpretation of these behavioural results. To overcome these issues, here we used a battery of behavioural tests to compare anxiety and memory in the same animals from the well-established inbred model of Genetic Absence Epilepsy Rats from Strasbourg (GAERS), their inbred strain of Non-Epileptic Control (NEC) strain (that lack ASs) and normal outbred Wistar rats. We found that GAERS do not exhibit increased anxiety-like behavior and neophobia compared to both NEC and Wistar rats. In contrast, GAERS show decreased spontaneous alternation, spatial working memory and cross-modal object recognition compared to both NEC and Wistar rats. Furthermore, GAERS preferentially used egocentric strategies to perform spatial memory tasks. In summary, these results provide solid evidence of memory deficits in GAERS rats that do not depend on an anxiety or neophobic phenotype. Moreover, the presence of differences between NEC and Wistar rats stresses the need of using both outbred and inbred control rats in behavioural studies involving genetic models of ASs.

HCN channels and absence seizures.

Hyperpolarization-activation cyclic nucleotide-gated (HCN) channels were for the first time implicated in absence seizures (ASs) when an abnormal Ih (the current generated by these channels) was reported in neocortical layer 5 neurons of a mouse model. Genetic studies of large cohorts of children with Childhood Absence Epilepsy (where ASs are the only clinical symptom) have identified only 3 variants in HCN1 (one of the genes that code for the 4 HCN channel isoforms, HCN1-4), with one (R590Q) mutation leading to loss-of-function. Due to the multi-faceted effects that HCN channels exert on cellular excitability and neuronal network dynamics as well as their modulation by environmental factors, it has been difficult to identify the detailed mechanism by which different HCN isoforms modulate ASs. In this review, we systematically and critically analyze evidence from established AS models and normal non-epileptic animals with area- and time-selective ablation of HCN1, HCN2 and HCN4. Notably, whereas knockout of rat HCN1 and mouse HCN2 leads to the expression of ASs, the pharmacological block of all HCN channel isoforms abolishes genetically determined ASs. These seemingly contradictory results could be reconciled by taking into account the well-known opposite effects of Ih on cellular excitability and network function. Whereas existing evidence from mouse and rat AS models indicates that pan-HCN blockers may provide a novel approach for the treatment of human ASs, the development of HCN isoform-selective drugs would greatly contribute to current research on the role for these channels in ASs generation and maintenance as well as offer new potential clinical applications.

Higher-order thalamic nuclei facilitate the generalization and maintenance of spike-and-wave discharges of absence seizures.

Spike-and-wave discharges (SWDs), generated by the cortico-thalamo-cortical (CTC) network, are pathological, large amplitude oscillations and the hallmark of absence seizures (ASs). SWDs begin in a cortical initiation network in both humans and animal models, including the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), where it is located in the primary somatosensory cortex (S1). The behavioral manifestation of an AS occurs when SWDs spread from the cortical initiation site to the whole brain, however, the mechanisms behind this rapid propagation remain unclear. Here we investigated these processes beyond the principal CTC network, in higher-order (HO) thalamic nuclei (lateral posterior (LP) and posterior (PO) nuclei) since their diffuse connectivity and known facilitation of intracortical communications make these nuclei key candidates to support SWD generation and maintenance. In freely moving GAERS, multi-site LFP in LP, PO and multiple cortical regions revealed a novel feature of SWDs: during SWDs there are short periods (named SWD-breaks) when cortical regions far from S1, such the primary visual cortex (V1), become transiently unsynchronized from the ongoing EEG rhythm. Inactivation of HO nuclei with local muscimol injections or optogenetic perturbation of HO nuclei activity increased the occurrence of SWD-breaks and the former intervention also increased the SWD propagation-time from S1. The neural underpinnings of these findings were explored further by silicon probe recordings from single units of PO which uncovered two previously unknown groups of excitatory neurons based on their burst firing dynamics at SWD onset. Moreover, a switch from tonic to burst firing at SWD onset was shown to be an important feature since it was much less prominent for non-generalized events, i.e. SWDs that remained local to S1. Additionally, one group of neurons showed a reverse of this switch during SWD-breaks, demonstrating the importance of this firing pattern throughout the SWD. In summary, these results support the view that multiple HO thalamic nuclei are utilized at SWD onset and contribute to cortical synchrony throughout the paroxysmal discharge.

Decreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures.

Absence seizures are brief episodes of impaired consciousness, behavioral arrest, and unresponsiveness, with yet-unknown neuronal mechanisms. Here we report that an awake female rat model recapitulates the behavioral, electroencephalographic, and cortical functional magnetic resonance imaging characteristics of human absence seizures. Neuronally, seizures feature overall decreased but rhythmic firing of neurons in cortex and thalamus. Individual cortical and thalamic neurons express one of four distinct patterns of seizure-associated activity, one of which causes a transient initial peak in overall firing at seizure onset, and another which drives sustained decreases in overall firing. 40-60 s before seizure onset there begins a decline in low frequency electroencephalographic activity, neuronal firing, and behavior, but an increase in higher frequency electroencephalography and rhythmicity of neuronal firing. Our findings demonstrate that prolonged brain state changes precede consciousness-impairing seizures, and that during seizures distinct functional groups of cortical and thalamic neurons produce an overall transient firing increase followed by a sustained firing decrease, and increased rhythmicity.

Effects of Anti-Seizure Medication on Sleep Spindles and Slow Waves in Drug-Resistant Epilepsy.

There is a close bidirectional relationship between sleep and epilepsy. Anti-seizure medications (ASM) act to reduce seizure frequency but can also impact sleep; this remains a relatively unexplored field given the importance of sleep on seizure occurrence, memory consolidation, and quality of life. We compared the effect of poly-ASM treatment on a night of sleep compared to an unmedicated night in patients with drug-resistant epilepsy, where ASMs were withdrawn and later restored as part of their pre-surgical evaluation. Within-subject analysis between medicated and unmedicated nights showed ASMs increased spindle (11-16 Hz) power and decreased slow wave (0.1-2 Hz) amplitude. Spindles became less strongly coupled to slow waves in the ASM night compared to no-ASM night, with effects to both the phase and strength of coupling and correlated with slow wave reduction. These effects were not seen in age-matched controls from the same unit where ASMs were not changed between two nights. Overall, we found that ASM polytherapy not only changed specific sleep waveforms, but also the fine interplay of spindle/slow wave coupling. Since these sleep oscillations impact both seizure occurrence and memory consolidation, our findings provide evidence towards a decoupling impact of ASMs on sleep that should be considered in future studies of sleep and memory disruption in people with epilepsy.

Cannabinoid 1/2 Receptor Activation Induces Strain-Dependent Behavioral and Neurochemical Changes in Genetic Absence Epilepsy Rats From Strasbourg and Non-epileptic Control Rats.

Childhood absence epilepsy (CAE) is characterized by absence seizures, which are episodes of lack of consciousness accompanied by electrographic spike-wave discharges. About 60% of children and adolescents with absence seizures are affected by major neuropsychological comorbidities, including anxiety. Endocannabinoids and monoamines are likely involved in the pathophysiology of these CAE psychiatric comorbidities. Here, we show that the synthetic cannabinoid receptor type 1/2 (CB1/2R) agonist WIN 55,212-2 (2 mg/kg) has a strain-dependent effect on anxiety-like and motor behavior when assess in the hole board test and cerebral monoaminergic levels in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and their non-epileptic control (NEC) rat strain. Using quantitative and Temporal pattern (T-pattern) analyses, we found that WIN 55,212-2 did not affect the emotional status of GAERS, but it was anxiolytic in NEC. Conversely, WIN 55,212-2 had a sedative effect in GAERS but was ineffective in NEC. Moreover, vehicle-treated GAERS more motivated to explore by implementing more complex and articulated strategies. These behavioral changes correlate with the reduction of 5-HT in the hippocampus and substantia nigra (SN) and noradrenaline (NA) in the entopeduncular nucleus (EPN) in vehicle-treated GAERS compared to NEC rats, which could contribute to their low anxiety status and hypermotility, respectively. On the other hand, the increased level of NA in the EPN and 5-HT in the SN is consistent with an activation of the basal ganglia output-mediated motor suppression observed in WIN 55,212-2-treated GAERS rats. These data support the view of a strain-dependent alteration of the endocannabinoid system in absence epilepsy by adding evidence of a lower emotional responsiveness and a basal ganglia hypersensitivity to cannabinoids in GAERS compared to NEC rats.

The effect of cannabinoid receptor agonist WIN 55,212-2 on anxiety-like behavior and locomotion in a genetic model of absence seizures in the elevated plus-maze.

GAERS and NEC rats were treated with cannabinoid 1/2 receptor agonist WIN 55,212-2 2 mg/kg and tested on the Elevated Plus-Maze.

Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures.

(1) Background: Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5-4 Hz spike-wave discharges (SWDs) in the EEG. In addition to the thalamocortical system, where these pathological oscillations are generated, multiple neuronal circuits have been involved in their modulation and associated comorbidities including the serotonergic system. Neuronal activity in one of the major synaptic input structures to the brainstem dorsal raphé nucleus (DRN), the lateral hypothalamus (LH), has not been characterized. (2) Methods: We used viral tract tracing and optogenetics combined with in vitro and in vivo electrophysiology to assess the involvement of the LH in absence epilepsy in a genetic rodent model. (3) Results: We found that a substantial fraction of LH neurons project to the DRN of which a minority is GABAergic. The LH to DRN projection can lead to monosynaptic iGluR mediated excitation in DRN 5-HT neurons. Neuronal activity in the LH is coupled to SWDs. (4) Conclusions: Our results indicate that a brain area involved in the regulation of autonomic functions and heavily innervating the RN is involved in ASs. The decreased activity of LH neurons during SWDs could lead to both a decreased excitation and disinhibition in the DRN. These results support a long-range subcortical regulation of serotonergic neuromodulation during ASs and further our understanding of the state-dependence of these seizures and some of their associated comorbidities.

Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures.

OBJECTIVE: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a proabsence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, which is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection into the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. METHODS: We used electroencephalographic recordings in freely moving Genetic Absence Epilepsy Rats From Strasbourg (GAERSs) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected into the CIN and VB of GAERSs in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical Layer 5/6 and thalamocortical neurons, respectively. RESULTS: Oral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection into CIN abolished ASs and elicited small-amplitude 4-7-Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN channel-dependent properties of cortical Layer 5/6 pyramidal and thalamocortical neurons, respectively. SIGNIFICANCE: These results provide the first demonstration of the antiabsence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.

5-HT/GABA interaction in epilepsy.

Epilepsy is a neurological condition characterized by synchronous neuronal oscillations (seizures) in the electroencephalogram. Seizures are classified in focal or generalized (depending on the brain territory interested during seizures), and in convulsive and/or not convulsive (depending on the presence or not of involuntary movements). The current pharmacological treatments are mainly based on GABA modulation although different neurotransmitters are also involved in epilepsy, including serotonin. However despite much extensive progress in the understanding of epilepsy mechanisms, still, a percentage of people with epilepsy are pharmaco-resistant calling for the need for new therapeutic targets. Here we review preclinical and human evidence showing that serotonin modulates epilepsy that this likely happens via a major modulation/interaction with GABA.

5-HT/GABA interaction in neurodevelopment and plasticity.

The adult brain is the result of a multistages complex neurodevelopmental process involving genetic, molecular and microenvironmental factors as well as diverse patterns of electrical activity. In the postnatal life, immature neuronal circuits undergo an experience-dependent maturation during critical periods of plasticity, but the brain still retains plasticity during adult life. In all these stages, the neurotransmitter GABA plays a pivotal role. In this chapter, we will describe the interaction of 5-HT with GABA in regulating neurodevelopment and plasticity.

Current knowledge of SLC6A1-related neurodevelopmental disorders.

Advances in gene discovery have identified genetic variants in the solute carrier family 6 member 1 gene as a monogenic cause of neurodevelopmental disorders, including epilepsy with myoclonic atonic seizures, autism spectrum disorder and intellectual disability. The solute carrier family 6 member 1 gene encodes for the GABA transporter protein type 1, which is responsible for the reuptake of the neurotransmitter GABA, the primary inhibitory neurotransmitter in the central nervous system, from the extracellular space. GABAergic inhibition is essential to counterbalance neuronal excitation, and when significantly disrupted, it negatively impacts brain development leading to developmental differences and seizures. Aggregation of patient variants and observed clinical manifestations expand understanding of the genotypic and phenotypic spectrum of this disorder. Here, we assess genetic and phenotypic features in 116 individuals with solute carrier family 6 member 1 variants, the vast majority of which are likely to lead to GABA transporter protein type 1 loss-of-function. The knowledge acquired will guide therapeutic decisions and the development of targeted therapies that selectively enhance transporter function and may improve symptoms. We analysed the longitudinal and cell type-specific expression of solute carrier family 6 member 1 in humans and localization of patient and control missense variants in a novel GABA transporter protein type 1 protein structure model. In this update, we discuss the progress made in understanding and treating solute carrier family 6 member 1-related disorders thus far, through the concerted efforts of clinicians, scientists and family support groups.

Impairments in sensory-motor gating and information processing in a mouse model of Ehmt1 haploinsufficiency.

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders. Haploinsufficiency of EHMT1, encoding a histone methyltransferase, is associated with several neurodevelopmental disorders, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency (Ehmt1 D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to neurodevelopmental disorders. Specifically, we show that Ehmt1 D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory, and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity. The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in Ehmt1 D6Cre/+ matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of Grin1 mRNA expression in Ehmt1 D6Cre/+ hippocampus, suggests that Ehmt1 haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced Ehmt1 dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the neurodevelopmental disorders associated with EHMT1 haploinsufficiency.

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases.

Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures.

Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

Absence of Neuronal Response Modulation with Familiarity in Perirhinal Cortex.

The perirhinal cortex (PRH) is considered a crucial cortical area for familiarity memory and electrophysiological studies have reported the presence of visual familiarity encoding neurons in PRH. However, recent evidence has questioned the existence of these neurons. Here, we used a visual task in which head-restrained mice were passively exposed to oriented gratings or natural images. Evoked potentials and single-unit recordings showed evoked responses to novelty in V1 under some conditions. However, the PRH showed no response modulation with respect to familiarity under a variety of different conditions or retention delays. These results indicate that the PRH does not contribute to familiarity/novelty encoding using passively exposed visual stimuli.