Asynchronous suppression of visual cortex during absence seizures

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.

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

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.688905 ◽

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.

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Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures

International Journal of Molecular Sciences ◽

10.3390/ijms22179466 ◽

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.

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Daily rhythms of seizure activity and behavior in a model of atypical absence epilepsy

Epilepsy & Behavior ◽

10.1016/j.yebeh.2006.08.019 ◽

2006 ◽

Vol 9 (4) ◽

pp. 564-572 ◽

Cited By ~ 22

Author(s):

Lee S. Stewart ◽

Eduard Bercovici ◽

Ruchica Shukla ◽

Irina Serbanescu ◽

Vasan Persad ◽

...

Keyword(s):

Seizure Activity ◽

Absence Epilepsy ◽

Daily Rhythms ◽

Atypical Absence ◽

And Behavior

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

10.1101/2021.04.20.440390 ◽

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.

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Levetiracetam and Rufinamide are effective at supressing spike and wave seizure activity in an in vitro model of absence epilepsy

10.1101/298711 ◽

2018 ◽

Author(s):

Virdziniha Todorova ◽

Georgina Ford ◽

Roger D. Traub ◽

Miles. A. Whittington ◽

Stephen. P. Hall

Keyword(s):

In Vitro Model ◽

Seizure Activity ◽

Absence Epilepsy ◽

Absence Seizures ◽

Clinical Burden ◽

Different Types ◽

Vitro Model ◽

Atypical Absence ◽

Component Amplitude

AbstractSpike-and-wave discharges (SpW) are seen in absence-type epilepsies. They are heterogeneous in terms of their clinical burden and their electrographic signature, which is used to classify different types of absence seizures; typical absence, in which SpW frequency is 3-4Hz and atypical absence, which shows a slower 1-2Hz frequency. Treatment of SpW varies dependent upon the syndrome, but both Valproic Acid (VPA) and Ethosuximide (ESM) are shown to be effective in controlling typical absence seizures. Other anti-epileptic’s (AED’s), Levetiracetam (LEV) and Rufinamide (RUF), have shown promise in treating absence epilepsies and their associated syndromes. Here we examine the efficacy of these AED’s on an in vitro model of SpW.Both LEV and RUF show an effective reduction in both the number of SpW events and the spike component amplitude; VPA shows no effect, whilst ESM enhances the spike amplitude. Phenytoin exacerbates the SpW activity, increasing both the number of SpW, amplitude of the SpW and the number of spikes within each event. These data suggest that both LEV and RUF could be effective in the treatment of absence-type epilepsies. They also suggest this model could be an effective tool to test other AED’s aimed at treating atypical absence syndromes.

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Spike‐wave discharges in absence epilepsy: segregation of electrographic components reveals distinct pathways of seizure activity

The Journal of Physiology ◽

10.1113/jp279483 ◽

2020 ◽

Vol 598 (12) ◽

pp. 2397-2414 ◽

Cited By ~ 2

Author(s):

Jonas Terlau ◽

Jenq‐Wei Yang ◽

Zeinab Khastkhodaei ◽

Thomas Seidenbecher ◽

Heiko J. Luhmann ◽

...

Keyword(s):

Seizure Activity ◽

Absence Epilepsy ◽

Spike Wave Discharges ◽

Spike Wave

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Mature parvalbumin interneuron function in prefrontal cortex requires activity during a postnatal sensitive period

10.1101/2021.03.04.433943 ◽

2021 ◽

Author(s):

Sarah E Canetta ◽

Emma S Holt ◽

Laura J Benoit ◽

Eric Teboul ◽

R. Todd Ogden ◽

...

Keyword(s):

Prefrontal Cortex ◽

Sensitive Period ◽

Network Function ◽

Parvalbumin Interneuron ◽

Circuit Integration ◽

Circuit Function ◽

And Behavior ◽

Activity Dependent

Sensitive periods in which experience-driven changes in activity persistently shape circuit function are well-described in sensory cortex. Whether comparable periods govern the development of associative cortical areas, like the prefrontal cortex, remains unclear. Here, we focus on the role of activity in the maturation and circuit integration of prefrontal parvalbumin-expressing interneurons, as these cells play an essential role in sensory cortical maturation and develop in lockstep with overall prefrontal circuit function. We found that transiently decreasing prefrontal parvalbumin activity during peripubertal and adolescent development results in persistent impairments in adult functional connectivity, in vivo network function and set-shifting behavior that can be rescued by targeted activation of these interneurons in the adult animal. In contrast, comparable adult inhibition had no lasting effects. These findings identify an activity-dependent sensitive period for prefrontal parvalbumin maturation and highlight how abnormal parvalbumin activity early in life can persistently alter adult circuit function and behavior.

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Onset of polyspike complexes in a mean-field model of human electroencephalography and its application to absence epilepsy

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2008.0255 ◽

2009 ◽

Vol 367 (1891) ◽

pp. 1145-1161 ◽

Cited By ~ 75

Author(s):

Frank Marten ◽

Serafim Rodrigues ◽

Oscar Benjamin ◽

Mark P Richardson ◽

John R Terry

Keyword(s):

Systematic Study ◽

Field Model ◽

Seizure Activity ◽

Mean Field ◽

Absence Epilepsy ◽

Wave Activity ◽

Clinical Tool ◽

Mean Field Model ◽

Different Types ◽

Spike Wave

In this paper, we introduce a modification of a mean-field model used to describe the brain's electrical activity as recorded via electroencephalography (EEG). The focus of the present study is to understand the mechanisms giving rise to the dynamics observed during absence epilepsy, one of the classical generalized syndromes. A systematic study of the data from a number of different subjects with absence epilepsy demonstrates a wide variety of dynamical phenomena in the recorded EEG. In addition to the classical spike and wave activity, there may be polyspike and wave, wave spike or even no discernible spike–wave onset during seizure events. The model we introduce is able to capture all of these different phenomena and we describe the bifurcations giving rise to these different types of seizure activity. We argue that such a model may provide a useful clinical tool for classifying different subclasses of absence epilepsy.

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Etanercept rescues cognitive deficits, depression-like symptoms, and spike-wave discharge incidence in WAG/Rij rat model of absence epilepsy

Epilepsy & Behavior ◽

10.1016/j.yebeh.2020.107532 ◽

2021 ◽

Vol 115 ◽

pp. 107532

Author(s):

Ayşe Karson ◽

Tijen Utkan ◽

Tuğçe Demirtaş Şahin ◽

Fuat Balcı ◽

Sertan Arkan ◽

...

Keyword(s):

Cognitive Deficits ◽

Rat Model ◽

Absence Epilepsy ◽

Wave Discharge ◽

Spike Wave

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Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development

Molecular Autism ◽

10.1186/s13229-021-00432-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

J. Ellegood ◽

S. P. Petkova ◽

A. Kinman ◽

L. R. Qiu ◽

A. Adhikari ◽

...

Keyword(s):

Corpus Callosum ◽

Ex Vivo ◽

Chromatin Modification ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Social Deficits ◽

Altered Expression ◽

Developmental Growth ◽

And Behavior

Abstract Background One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. Methods A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. Results We validated decreased Arid1b mRNA and protein in Arid1b+/− mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b+/− cerebellum. During neonatal development, Arid1b+/− mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b+/− mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b+/− mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male–female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b+/− mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. Limitations The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. Conclusions This study represents a full validation and investigation of a novel model of Arid1b+/− haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

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