scholarly journals Chemogenetic Activation of Feed-Forward Inhibitory Parvalbumin-Expressing Interneurons in the Cortico-Thalamocortical Network During Absence Seizures

2021 ◽  
Vol 15 ◽  
Author(s):  
Sandesh Panthi ◽  
Beulah Leitch
Keyword(s):  
Absence Epilepsy ◽  
Designer Drug ◽  
Absence Seizure ◽  
Absence Seizures ◽  
Feed Forward ◽  
Video Recordings ◽  
Intraperitoneal Dose ◽  
Spike Wave Discharges ◽  
The Impact

Parvalbumin-expressing (PV+) interneurons are a subset of GABAergic inhibitory interneurons that mediate feed-forward inhibition (FFI) within the cortico-thalamocortical (CTC) network of the brain. The CTC network is a reciprocal loop with connections between cortex and thalamus. FFI PV+ interneurons control the firing of principal excitatory neurons within the CTC network and prevent runaway excitation. Studies have shown that generalized spike-wave discharges (SWDs), the hallmark of absence seizures on electroencephalogram (EEG), originate within the CTC network. In the stargazer mouse model of absence epilepsy, reduced FFI is believed to contribute to absence seizure genesis as there is a specific loss of excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at synaptic inputs to PV+ interneurons within the CTC network. However, the degree to which this deficit is directly related to seizure generation has not yet been established. Using chemogenetics and in vivo EEG recording, we recently demonstrated that functional silencing of PV+ interneurons in either the somatosensory cortex (SScortex) or the reticular thalamic nucleus (RTN) is sufficient to generate absence-SWDs. Here, we used the same approach to assess whether activating PV+ FFI interneurons within the CTC network during absence seizures would prevent or reduce seizures. To target these interneurons, mice expressing Cre recombinase in PV+ interneurons (PV-Cre) were bred with mice expressing excitatory Gq-DREADD (hM3Dq-flox) receptors. An intraperitoneal dose of pro-epileptic chemical pentylenetetrazol (PTZ) was used to induce absence seizure. The impact of activation of FFI PV+ interneurons during seizures was tested by focal injection of the “designer drug” clozapine N-oxide (CNO) into either the SScortex or the RTN thalamus. Seizures were assessed in PVCre/Gq-DREADD animals using EEG/video recordings. Overall, DREADD-mediated activation of PV+ interneurons provided anti-epileptic effects against PTZ-induced seizures. CNO activation of FFI either prevented PTZ-induced absence seizures or suppressed their severity. Furthermore, PTZ-induced tonic-clonic seizures were also reduced in severity by activation of FFI PV+ interneurons. In contrast, administration of CNO to non-DREADD wild-type control animals did not afford any protection against PTZ-induced seizures. These data demonstrate that FFI PV+ interneurons within CTC microcircuits could be a potential therapeutic target for anti-absence seizure treatment in some patients.

scholarly journals Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Kathryn A Salvati ◽  
George MPR Souza ◽  
Adam C Lu ◽  
Matthew L Ritger ◽  
Patrice Guyenet ◽  
...  
Keyword(s):  
Respiratory Alkalosis ◽  
Absence Epilepsy ◽  
Ph Sensitive ◽  
Absence Seizure ◽  
Patient Response ◽  
Absence Seizures ◽  
Intralaminar Nuclei ◽  
Highly Sensitive ◽  
Intralaminar Thalamus ◽  
Spike Wave Discharges

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. By utilizing gas exchange manipulations and optogenetics in the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

scholarly journals Respiratory Alkalosis Provokes Spike-Wave Discharges in Seizure- Prone Rats

2021 ◽  
Author(s):  
Kathryn Salvati ◽  
George M.P.R. Souza ◽  
Adam C Lu ◽  
Matthew L Ritger ◽  
Patrice Guyenet ◽  
...  
Keyword(s):  
Respiratory Alkalosis ◽  
Absence Epilepsy ◽  
Ph Sensitive ◽  
Absence Seizure ◽  
Patient Response ◽  
Absence Seizures ◽  
Intralaminar Nuclei ◽  
Highly Sensitive ◽  
Intralaminar Thalamus ◽  
Spike Wave Discharges

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. Using the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

scholarly journals Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures

2021 ◽  
Vol 22 (17) ◽  
pp. 9466
Author(s):  
Péter Sere ◽  
Nikolett Zsigri ◽  
Timea Raffai ◽  
Szabina Furdan ◽  
Fanni Győri ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Lateral Hypothalamus ◽  
Brain Area ◽  
State Dependence ◽  
Absence Epilepsy ◽  
Absence Seizures ◽  
Spike Wave Discharges ◽  
Genetically Determined

(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.

scholarly journals Cortical Tonic Inhibition Regulates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy

2017 ◽  
Author(s):  
Kile P. Mangan ◽  
Aaron B. Nelson ◽  
Steven Petrou ◽  
Chiara Cirelli ◽  
Mathew V. Jones
Keyword(s):  
Absence Epilepsy ◽  
Tonic Inhibition ◽  
Absence Seizure ◽  
Optimum Level ◽  
Normal Functioning ◽  
Absence Seizures ◽  
Pharmacological Blockade ◽  
Eeg Recordings ◽  
Wave Discharge ◽  
Video Eeg

ABSTRACTSynchronous and bilateral spike-and-wave discharges accompany nonconvulsive behavioral and cognitive arrest during seizures associated with absence epilepsy. Previous investigation of multiple absence animal models suggests that the underlying cause of absence seizures is an increase in thalamic inhibitory tonic currents. In contrast, in this study we provide evidence that the level of cortical tonic inhibition also regulates absence seizure expression. Using continuous video-EEG recordings to monitor absence seizures and spike-and-wave discharge expression we show that pharmacological blockade of cortical tonic inhibition provokes absence seizures in wild-type mice. Furthermore, we show that pharmacological rescue of cortical tonic inhibition in an absence mouse (γ2R43Q) model, which lacks tonic inhibition, suppresses absence seizure and spike-and-wave discharge expression. Collectively, these results suggest an optimum level of tonic inhibition in the thalamocortical circuit is required for normal functioning and that a deviation from this optimum results in aberrant thalamocortical function, SWDs and absence seizures.

scholarly journals Full bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene micro-transistor depth neural probes

2021 ◽  
Author(s):  
Andrea Bonaccini Calia ◽  
Eduard Masvidal-Codina ◽  
Trevor M. Smith ◽  
Nathan Schäfer ◽  
Daman Rathore ◽  
...  
Keyword(s):  
High Frequency ◽  
Epileptiform Activity ◽  
Epileptic Activity ◽  
Absence Epilepsy ◽  
Neural Probes ◽  
Chemically Induced ◽  
Metal Microelectrode ◽  
Spike Wave Discharges ◽  
Implanted Devices

ABSTRACTMapping the entire frequency bandwidth of neuronal oscillations in the brain is of paramount importance for understanding physiological and pathological states. The ability to record simultaneously infraslow activity (<0.1 Hz) and higher frequencies (0.1-600 Hz) using the same recording electrode would particularly benefit epilepsy research. However, commonly used metal microelectrode technology is not well suited for recording infraslow activity. Here we use flexible graphene depth neural probes (gDNP), consisting of a linear array of graphene microtransistors, to concurrently record infraslow and high frequency neuronal activity in awake rodents. We show that gDNPs can reliably record and map with high spatial resolution seizures, post-ictal spreading depolarisation, and high frequency epileptic activity through cortical laminae to the CA1 layer of the hippocampus in a mouse model of chemically-induced seizures. We demonstrate functionality of chronically implanted devices over 10 weeks by recording with high fidelity spontaneous spike-wave discharges and associated infraslow activity in a rat model of absence epilepsy. Altogether, our work highlights the suitability of this technology for in vivo electrophysiology research, in particular, to examine the contributions of infraslow activity to seizure initiation and termination.

scholarly journals Cerebellar Contribution to Absence Epilepsy

2020 ◽  
Author(s):  
Leonid S. Godlevsky ◽  
Oleh R. Pinyazhko ◽  
Olesya B. Poshyvak
Keyword(s):  
Epileptic Activity ◽  
Absence Epilepsy ◽  
Absence Seizure ◽  
Imaging Data ◽  
Optogenetic Stimulation ◽  
Different Types ◽  
Spike Wave Discharges ◽  
Deep Brain ◽  
Spike Wave

ABSTRACTThe new aggregate data analyses revealed the earlier missing role played by the cerebellum long-term electrical stimulation in the absence epilepsy. Neurophysiologic data gained by authors favor that cerebellar serial deep brain stimulation (DBS) (100 Hz) causes the transformation of penicillin-induced cortical focal discharges into prolonged 3,5-3,75 sec oscillations resembling spike-wave discharges (SWD) in cats. Such SWDs were not organized in the form of bursts and persisted continuously after stimulation. Therefore the appearance of prolonged periods of SWD is regarded as a tonic cerebellar influence upon pacemaker of SWD and might be caused by the long-lasting DBS-induced increase of GABA-ergic extrasynaptic inhibition in forebrain networks. At the same time, cerebellar DBS high-frequency (100 Hz) suppressed bursts of SWD observed during the phase of stimulation. Different types of cerebellar DBS upon epileptic activity emphasized the absence seizure facilitation discussed with the reviewed data on optogenetic stimulation, neuronal activity of cerebellar structures, and functional magnetic resonance imaging data.

scholarly journals Asynchronous suppression of visual cortex during absence seizures

2018 ◽  
Author(s):  
Jochen Meyer ◽  
Atul Maheshwari ◽  
Jeffrey Noebels ◽  
Stelios Smirnakis
Keyword(s):  
Visual Cortex ◽  
Seizure Activity ◽  
Absence Epilepsy ◽  
Absence Seizures ◽  
Pairwise Correlation ◽  
Network Function ◽  
Calcium Indicator ◽  
And Behavior ◽  
Spike Wave

AbstractAbsence epilepsy is a common childhood disorder featuring frequent cortical spike-wave seizures with a loss of awareness and behavior. Using the calcium indicator GCaMP6 with in vivo 2-photon cellular microscopy and simultaneous electrocorticography, we examined the collective activity profiles of individual neurons and surrounding neuropil across all layers in V1 during spike-wave seizure activity over prolonged periods in stargazer mice. We show that most (∼80%) neurons in all cortical layers reduce their activity during seizures, whereas a smaller pool activates or remains neutral. Unexpectedly, ictal participation of identified single unit activity is not fixed, but fluctuates on a flexible time scale across seizures. Pairwise correlation analysis of calcium activity reveals a surprising lack of synchrony among neurons and neuropil patches in all layers during seizures. Our results demonstrate an asynchronous suppression of visual cortex during absence seizures, with major implications for understanding cortical network function during EEG states of reduced awareness.

scholarly journals Pretreatment seizure semiology in childhood absence epilepsy

Neurology ◽  
2017 ◽  
Vol 89 (7) ◽  
pp. 673-679 ◽  
Author(s):  
Sudha Kilaru Kessler ◽  
Shlomo Shinnar ◽  
Avital Cnaan ◽  
Dennis Dlugos ◽  
Joan Conry ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Absence Epilepsy ◽  
Absence Seizure ◽  
Seizure Freedom ◽  
Childhood Absence Epilepsy ◽  
Short Term ◽  
Short Term Treatment ◽  
Absence Seizures ◽  
Seizure Semiology ◽  
Eye Involvement

Objective:To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes.Methods:For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit.Results:Video of 1,932 electrographic absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%–84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern.Conclusions:Almost all absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome.

scholarly journals Augmentation of Tonic GABAAInhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAAReceptors

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Adam C. Errington ◽  
David W. Cope ◽  
Vincenzo Crunelli
Keyword(s):  
Epileptic Seizures ◽  
Absence Epilepsy ◽  
Vital Role ◽  
Gaba Uptake ◽  
Absence Seizure ◽  
Pharmacological Agents ◽  
Absence Seizures ◽  
Inverse Agonists ◽  
Potential Therapeutic Role ◽  
Necessary And Sufficient

It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABAAreceptors (eGABAAR) and augmented “tonic” GABAAinhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy. Moreover, evidence from monogenic mouse models (stargazer/lethargic) and the polygenic Genetic Absence Epilepsy Rats from Strasbourg (GAERS) indicate that the mechanism underlying eGABAAR gain of function is nonneuronal in nature and results from a deficiency in astrocytic GABA uptake through the GAT-1 transporter. These results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy. Moreover, they explain why pharmacological agents that enhance GABA receptor function can initiate or exacerbate absence seizures and suggest a potential therapeutic role for inverse agonists at eGABAARs in absence epilepsy.

scholarly journals Decreased overall neuronal activity in a rodent model of impaired consciousness during absence seizures

2021 ◽  
Author(s):  
Cian McCafferty ◽  
Benjamin Gruenbaum ◽  
Renee Tung ◽  
Jing-Jing Li ◽  
Peter Salvino ◽  
...  
Keyword(s):  
Absence Epilepsy ◽  
Neuronal Firing ◽  
Initial Increase ◽  
Loss Of Consciousness ◽  
Absence Seizures ◽  
Apparent Loss ◽  
Neuronal Mechanisms ◽  
Spike Wave Discharges ◽  
Initial Peak ◽  
Spike Wave

AbstractAbsence seizures are characterized by a brief behavioural impairment including apparent loss of consciousness. Neuronal mechanisms determining the behavioural impairment of absence seizures remain unknown, and their elucidation might highlight therapeutic options for reducing seizure severity. However, recent studies have questioned the similarity of animal spike-wave-discharges (SWD) to human absence seizures both behaviourally and neuronally. Here, we report that Genetic Absence Epilepsy Rats from Strasbourg recapitulate the decreased neuroimaging signals and loss of consciousness characteristic of human absence seizures. Overall neuronal firing is decreased but rhythmic in the somatosensory cortex and thalamus during these seizures. Interestingly, individual neurons in both regions tend to consistently express one of four distinct patterns of seizure-associated activity. These patterns differ in firing rate dynamics and in rhythmicity during seizure. One group of neurons showed a transient initial peak in firing at SWD onset, accounting for the brief initial increase in overall neuronal firing seen in cortex and thalamus. The largest group of neurons in both cortex and thalamus showed sustained decreases in firing during SWD. Other neurons showed either sustained increases or no change in firing. These findings suggest that certain classes of cortical and thalamic neurons may be particularly responsible for the paroxysmal oscillations and consequent loss of consciousness in absence epilepsy.

Sign in / Sign up

Export Citation Format

Share Document