scholarly journals Tonic Inhibition is Abolished in GABAA Receptor γ2R43Q Knock-in Mice with Absence Epilepsy and Febrile Seizures

2017 ◽  
Author(s):  
Kile P. Mangan ◽  
Wyatt B. Potter ◽  
Aaron B. Nelson ◽  
Steve Petrou ◽  
Stephen M. Johnson ◽  
...  
Keyword(s):  
Brain Slices ◽  
Febrile Seizures ◽  
Absence Epilepsy ◽  
Protein Quantification ◽  
Tonic Inhibition ◽  
Optimum Level ◽  
Absence Seizures ◽  
Ventrobasal Thalamus ◽  
Patch Clamp Electrophysiology ◽  
Necessary And Sufficient

ABSTRACTThe γ2R43Q GABAA receptor mutation confers absence epilepsy in humans, and γ2R43Q knock-in mice (RQ) display absence seizures and generalized spike-and-wave discharges reminiscent of their human counterparts. Previous work on several rodent models led to the conclusion that elevated tonic inhibition in thalamic neurons is necessary and sufficient to produce typical absence epilepsy. In contrast, here we used patch-clamp electrophysiology in brain slices to show that RQ mice entirely lack tonic inhibition in principal cells of layer II/III somatosensory cortex and ventrobasal thalamus. Additionally, protein quantification and multielectrode electrophysiology show that the mutation interferes with trafficking of GABAA receptor subunits involved in generating tonic currents, leading to increased cortical firing and decreased thalamic bursting rates. Together with previous work, our results suggest that an optimum level of tonic inhibition is required for normal thalamocortical function, such that deviations in either direction away from this optimum enhance susceptibility to absence seizures.

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 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 Cortical alterations in a model for absence epilepsy and febrile seizures: In vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation

2015 ◽  
Vol 77 ◽  
pp. 62-70 ◽  
Author(s):  
Jens Witsch ◽  
Daniel Golkowski ◽  
Thomas T.G. Hahn ◽  
Steven Petrou ◽  
Hartwig Spors
Keyword(s):  
Febrile Seizures ◽  
Absence Epilepsy ◽  
Gaba A

Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: Study of the leucine-glutamate cycle

2001 ◽  
Vol 66 (5) ◽  
pp. 923-930 ◽  
Author(s):  
Franck Dufour ◽  
Katarzyna A. Nalecz ◽  
Maciej J. Nalecz ◽  
Astrid Nehlig
Keyword(s):  
Genetic Model ◽  
Absence Epilepsy ◽  
Absence Seizures

scholarly journals Seizure Exacerbation by Antiepileptic Drugs

2005 ◽  
Vol 5 (5) ◽  
pp. 192-193 ◽  
Author(s):  
Jacqueline A. French
Keyword(s):  
Antiepileptic Drugs ◽  
De Novo ◽  
Focal Epilepsy ◽  
Juvenile Myoclonic Epilepsy ◽  
Absence Epilepsy ◽  
Absence Seizures ◽  
Incorrect Diagnosis ◽  
Juvenile Absence Epilepsy ◽  
Generalized Epilepsy

Worsening of Seizures by Oxcarbazepine in Juvenile Idiopathic Generalized Epilepsies Gelisse P, Genton P, Kuate C, Pesenti A, Baldy-Moulinier M, Crespel A Epilepsia 2004;45:1282–1286 Purpose Several studies have shown that carbamazepine (CBZ) may aggravate idiopathic generalized epilepsy (IGE). Oxcarbazepine (OXC) is a new drug chemically related to CBZ. We report six cases of juvenile IGE with a clear aggravation by OXC. Methods We retrospectively studied all patients with IGE first referred to our epilepsy department between January 2001 and June 2003 and treated with OXC. Results During this period, six patients were identified. All had an aggravation of their epilepsy in both clinical and EEG activities. OXC had been used because of an incorrect diagnosis of focal epilepsy or generalized tonic–clonic seizures (GTCSs) of undetermined origin (no syndromic classification of the epilepsy). Before OXC, only one patient had experienced a worsening of seizures with an inadequate drug (carbamazepine; CBZ). Four had juvenile myoclonic epilepsy, one had juvenile absence epilepsy, and one had IGE that could not be classified into a precise syndrome. OXC (dosage range, 300–1,200 mg/day) was used in monotherapy in all of them except for one patient. Aggravation consisted of a clear aggravation of myoclonic jerks (five cases) or de novo myoclonic jerks (one case). Three patients had exacerbation of absence seizures. One patient had worsened dramatically and had absence status, and one had de novo absences after OXC treatment. The effects of OXC on GTCSs were less dramatic, with no worsening in frequency in three and a slight increase in three. Conclusions OXC can be added to the list of antiepileptic drugs that can exacerbate myoclonic and absence seizures in IGE.

scholarly journals L’absence épileptique de l’enfance dont le controle nécessite plus d’un medicament.

2008 ◽  
Vol 35 (3) ◽  
pp. 297-300 ◽  
Author(s):  
B. Nadler ◽  
M. I. Shevell
Keyword(s):  
Seizure Control ◽  
Absence Epilepsy ◽  
Control Group ◽  
Epilepsy Syndrome ◽  
Absence Seizures ◽  
Significant Difference ◽  
Age Of Diagnosis ◽  
Group 2 ◽  
Group 1

Introduction:Absence epilepsy is the most common primary generalized epilepsy syndrome encountered in pediatric practice. Treatment is pharmacologically specific and usually successful with a single medication. The objective of this study was to identify any clinical or electroencephalographic features at initial presentation in a consecutive cohort of children with absence epilepsy that may be associated with the need for a second medication.Methods:A computerized pediatric neurology database (1991-2007 inclusive) was retrospectively searched for all patients with typical absence seizures, 3 Hz spike and wave on EEG and no apparent symptomatic etiology who were over the age of two years at seizure onset with at least one year of follow-up. All such children were then divided into two groups; a) those requiring a single medication for seizure control (Group 1), and b) those requiring two medications for seizure control despite optimal management with the initial medication as determined by serum drug monitoring (Group 2). Clinical and electrographic features evident at diagnosis were then contrasted between Group 1 and 2.Results:Seventy-five children with absence seizures were initially identified with 52 meeting the study’s inclusion and none of the exclusion criteria. Of these 52 children, 43 required a single medication for seizure control (Group 1), while 9 required two or more medications for seizure control (Group 2). A significant difference (p<0.05) was apparent between Group 1 and 2 with respect to gender (16/43 males vs 8/9 males) and mean age of diagnosis (8.19 years +/− 3.00 vs 6.06 years +/− 2.22). Age of onset of seizures, interval duration of seizures prior to treatment initiation, duration of seizures, presence of automatisms, family history, presence of co-morbid conditions and EEG findings were not found to be significantly different between the two Groups.Conclusions:Male gender and an earlier age of diagnosis is associated with the need for two medications for seizure control in children with absence epilepsy. This observation may suggest the need for more intensive early programmatic follow-up for young male children with newly diagnosed absence epilepsy to effect more rapid attainment of seizure control.

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.

Sign in / Sign up

Export Citation Format

Share Document