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Russell J. Ferland - One of the best experts on this subject based on the ideXlab platform.

  • dissociation of spontaneous seizures and brainstem seizure thresholds in mice exposed to eight Flurothyl induced generalized seizures
    Epilepsia Open, 2017
    Co-Authors: Sridhar B. Kadiyala, Russell J. Ferland
    Abstract:

    SummaryObjective C57BL/6J mice exposed to eight Flurothyl-induced generalized clonic seizures exhibit a change in seizure phenotype following a 28-day incubation period and subsequent Flurothyl rechallenge. Mice now develop a complex seizure semiology originating in the forebrain and propagating into the brainstem seizure network (a forebrain→brainstem seizure). In contrast, this phenotype change does not occur in seizure-sensitive DBA/2J mice. The underlying mechanism(s) was the focus of these studies. Methods DBA2/J mice were exposed to eight Flurothyl-induced seizures (1/day) followed by 24-hour video-electroencephalographic recordings for 28-days. Forebrain and brainstem seizure thresholds were determined in C57BL/6J and DBA/2J mice following one or eight Flurothyl-induced seizures, or after eight Flurothyl-induced seizures, a 28-day incubation period, and final Flurothyl rechallenge. Results Similar to C57BL/6J mice, DBA2/J mice expressed spontaneous seizures. However, unlike C57BL/6J mice, DBA2/J mice continued to have spontaneous seizures without remission. Since DBA2/J mice do not express forebrain→brainstem seizures following Flurothyl rechallenge after a 28-day incubation period, this indicated that spontaneous seizures were not sufficient for the evolution of forebrain→brainstem seizures. Therefore, we determined whether brainstem seizure thresholds were changing during this repeated-Flurothyl model and whether this could account for the expression of forebrain→brainstem seizures. Brainstem seizure thresholds were not different between C57BL/6J and DBA/2J mice on day one or on the last induction seizure trial (day eight). However, brainstem seizure thresholds did differ significantly on Flurothyl rechallenge (day 28) with DBA/2J mice showing no lowering of their brainstem seizure thresholds. Significance These results demonstrated that DBA/2J mice exposed to the repeated-Flurothyl model develop spontaneous seizures without evidence of seizure remission and provide a new model of epileptogenesis. Moreover, these findings indicated that the transition of forebrain ictal discharge into the brainstem seizure network occurs due to changes in brainstem seizure thresholds that are independent of spontaneous seizure expression. This article is protected by copyright. All rights reserved.

  • Dissociation of spontaneous seizures and brainstem seizure thresholds in mice exposed to eight Flurothyl‐induced generalized seizures
    Epilepsia open, 2016
    Co-Authors: Sridhar B. Kadiyala, Russell J. Ferland
    Abstract:

    SummaryObjective C57BL/6J mice exposed to eight Flurothyl-induced generalized clonic seizures exhibit a change in seizure phenotype following a 28-day incubation period and subsequent Flurothyl rechallenge. Mice now develop a complex seizure semiology originating in the forebrain and propagating into the brainstem seizure network (a forebrain→brainstem seizure). In contrast, this phenotype change does not occur in seizure-sensitive DBA/2J mice. The underlying mechanism(s) was the focus of these studies. Methods DBA2/J mice were exposed to eight Flurothyl-induced seizures (1/day) followed by 24-hour video-electroencephalographic recordings for 28-days. Forebrain and brainstem seizure thresholds were determined in C57BL/6J and DBA/2J mice following one or eight Flurothyl-induced seizures, or after eight Flurothyl-induced seizures, a 28-day incubation period, and final Flurothyl rechallenge. Results Similar to C57BL/6J mice, DBA2/J mice expressed spontaneous seizures. However, unlike C57BL/6J mice, DBA2/J mice continued to have spontaneous seizures without remission. Since DBA2/J mice do not express forebrain→brainstem seizures following Flurothyl rechallenge after a 28-day incubation period, this indicated that spontaneous seizures were not sufficient for the evolution of forebrain→brainstem seizures. Therefore, we determined whether brainstem seizure thresholds were changing during this repeated-Flurothyl model and whether this could account for the expression of forebrain→brainstem seizures. Brainstem seizure thresholds were not different between C57BL/6J and DBA/2J mice on day one or on the last induction seizure trial (day eight). However, brainstem seizure thresholds did differ significantly on Flurothyl rechallenge (day 28) with DBA/2J mice showing no lowering of their brainstem seizure thresholds. Significance These results demonstrated that DBA/2J mice exposed to the repeated-Flurothyl model develop spontaneous seizures without evidence of seizure remission and provide a new model of epileptogenesis. Moreover, these findings indicated that the transition of forebrain ictal discharge into the brainstem seizure network occurs due to changes in brainstem seizure thresholds that are independent of spontaneous seizure expression. This article is protected by copyright. All rights reserved.

  • Analysis of Flurothyl-induced Myoclonus in Inbred Strains of Mice
    2015
    Co-Authors: Dominick Pap, Tara M. Anderson, Bruce J. Herron, Whitney S. Kukol, Russell J. Ferland
    Abstract:

    Myoclonus is often observed in epilepsy. It is characterized by sudden involuntary shock-like movements of the body (myoclonic jerks, MJs). This study examined whether epileptic myoclonus was under genetic control. Inbred strains of mice were administered eight daily Flurothyl exposures, a 28-day rest period, and a final Flurothyl retest. For all trials, the latency to the first MJ (threshold) and the number of MJs (MJ#) were recorded. The inbred strains that we examined exhibited significant variability in initial myoclonic response, and myoclonus across the eight Flurothyl exposures. C57BL/6J and DBA/2J mice displayed significantly different initial latencies to a MJ, MJ # preceding a generalized seizure (GS), and changes in MJ threshold and MJ # across the eight seizure trials. [C57BL/6JxDBA/2J] F1-hybrid mice showed an initial MJ threshold and decreases in MJ threshold over the eight trials, which were similar to C57BL/6J; however, F1-hybrids had an initial MJ # and trend in MJ # over the eight trials that were similar to DBA/2J. Decreases in MJ threshold and MJ # following multiple seizure trials, observed in C57BL/6J mice, were dependent on the expression of GSs and not on MJ occurrence. Our study is the first to document the potential for genetic heterogeneity of myoclonus in mice; we show that significant alterations in myocloni

  • spatiotemporal differences in the c fos pathway between c57bl 6j and dba 2j mice following Flurothyl induced seizures a dissociation of hippocampal fos from seizure activity
    Epilepsy Research, 2015
    Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Tara M. Anderson, Bruce J. Herron, Russell J. Ferland, Karina Tuz, Sachidhanand Jayakumar
    Abstract:

    Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final Flurothyl rechallenge. Two brain regions, the hippocampus and ventromedial nucleus of the hypothalamus (VMH), had significantly different Fos expression profiles following seizures. Fos expression was highly robust in B6 hippocampus following one seizure and remained elevated following multiple seizures. Conversely, there was an absence of Fos (and phospho-Erk) expression in D2 hippocampus following one generalized seizure that increased with multiple seizures. This lack of Fos expression occurred despite intracranial electroencephalographic recordings indicating that the D2 hippocampus propagated ictal discharge during the first Flurothyl seizure suggesting a dissociation of seizure discharge from Fos and phospho-Erk expression. Global transcriptional analysis confirmed a dysregulation of the c-fos pathway in D2 mice following 1 seizure. Moreover, global analysis of RNA expression differences between B6 and D2 hippocampus revealed a unique pattern of transcripts that were co-regulated with Fos in D2 hippocampus following 1 seizure. These expression differences could, in part, account for D2's seizure susceptibility phenotype. Following 8 seizures, a 28 day rest period, and a final Flurothyl rechallenge, ∼85% of B6 mice develop a more complex seizure phenotype consisting of a clonic-forebrain seizure that uninterruptedly progresses into a brainstem seizure. This seizure phenotype in B6 mice is highly correlated with bilateral Fos expression in the VMH and was not observed in D2 mice, which always express clonic-forebrain seizures upon Flurothyl retest. Overall, these results illustrate specific differences in protein and RNA expression in different inbred strains following seizures that precede the reorganizational events that affect seizure susceptibility and changes in seizure semiology over time.

  • Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following Flurothyl-induced seizures: a dissociation of hippocampal Fos from seizure activity
    Epilepsy research, 2014
    Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Tara M. Anderson, Bruce J. Herron, Karina Tuz, Sachidhanand Jayakumar, Russell J. Ferland
    Abstract:

    Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final Flurothyl rechallenge. Two brain regions, the hippocampus and ventromedial nucleus of the hypothalamus (VMH), had significantly different Fos expression profiles following seizures. Fos expression was highly robust in B6 hippocampus following one seizure and remained elevated following multiple seizures. Conversely, there was an absence of Fos (and phospho-Erk) expression in D2 hippocampus following one generalized seizure that increased with multiple seizures. This lack of Fos expression occurred despite intracranial electroencephalographic recordings indicating that the D2 hippocampus propagated ictal discharge during the first Flurothyl seizure suggesting a dissociation of seizure discharge from Fos and phospho-Erk expression. Global transcriptional analysis confirmed a dysregulation of the c-fos pathway in D2 mice following 1 seizure. Moreover, global analysis of RNA expression differences between B6 and D2 hippocampus revealed a unique pattern of transcripts that were co-regulated with Fos in D2 hippocampus following 1 seizure. These expression differences could, in part, account for D2's seizure susceptibility phenotype. Following 8 seizures, a 28 day rest period, and a final Flurothyl rechallenge, ∼85% of B6 mice develop a more complex seizure phenotype consisting of a clonic-forebrain seizure that uninterruptedly progresses into a brainstem seizure. This seizure phenotype in B6 mice is highly correlated with bilateral Fos expression in the VMH and was not observed in D2 mice, which always express clonic-forebrain seizures upon Flurothyl retest. Overall, these results illustrate specific differences in protein and RNA expression in different inbred strains following seizures that precede the reorganizational events that affect seizure susceptibility and changes in seizure semiology over time.

Gregory L. Holmes - One of the best experts on this subject based on the ideXlab platform.

  • Neonatal Seizures Induced Persistent Changes in Intrinsic Properties of CA1
    2013
    Co-Authors: Nathalie Villeneuve, Gregory L. Holmes, Yehzekiel Ben-ari, Jean-luc Gaiarsa
    Abstract:

    We investigated the effects of repeated early-life seizures induced by Flurothyl inhalation on intrinsic membrane properties of hippocampal pyramidal neurons from young rats (postnatal day 15–20). Intracellular recordings of CA1 and CA3 pyramidal neurons from Flurothyl-treated and control rats revealed no significant differences in resting membrane potential, input resistance, membrane time constant, and action potential characteristics. In CA1 pyramidal cells from Flurothyl-treated rats, the spike frequency adaptation and afterhyperpolarizing potential following a spike train were markedly reduced when compared with controls. In contrast, no significant alterations in the firing properties of CA3 pyramidal neurons were found. It is concluded that neonatal seizures lead to persistent changes in intrinsic membrane properties of CA1 pyramidal neurons. These alterations are consistent with an increase in neuronal excitability and may contribute to the behavioral deficit and epileptogenic predisposition observed in rats that experienced repeated neonatal seizures. Villeneuve N, Ben-Ari Y, Holmes GL, Gaiarsa J-L. Neonatal seizures induced persistent changes in intrinsic properties of CA1 rat hippocampal cells. Ann Neurol 2000;47:729–738 Both clinical and experimental studies have emphasized the age dependency of epilepsy with regard to the seizure susceptibility. Thus, the incidence of seizures i

  • Cognitive impairment following status epilepticus and recurrent seizures during early development: support for the “two-hit hypothesis”
    Epilepsy & behavior : E&B, 2004
    Co-Authors: Alexandra F. Hoffmann, Qian Zhao, Gregory L. Holmes
    Abstract:

    Prolonged seizures in immature rats result in minimal behavioral consequences when the animals are studied later in life. Likewise, early-onset seizures are associated with minimal morphological changes. However, it is known that seizures early in life result in changes in the brain that make it more vulnerable to subsequent seizure-induced injury (the so-called two-hit hypothesis). Whether this heightened vulnerability occurs immediately after the first seizure is not known. In this study, immature rats were exposed to status epilepticus (SE) followed by a series of 25 Flurothyl-induced seizures, SE alone, 25 Flurothyl-induced seizures alone, or no seizures. Rats exposed to SE and Flurothyl seizures performed significantly poorer in the water maze 2 weeks following the last seizure compared with the other groups. No histological lesions were seen in any of the four groups. This study suggests that SE renders the immature brain vulnerable to further seizure-induced injury and this enhanced vulnerability occurs very quickly after the SE.

  • Neonatal seizures induced persistent changes in intrinsic properties of CA1 rat hippocampal cells.
    Annals of neurology, 2000
    Co-Authors: Nathalie Villeneuve, Gregory L. Holmes, Yehzekiel Ben-ari, Jean-luc Gaiarsa
    Abstract:

    We investigated the effects of repeated early-life seizures induced by Flurothyl inhalation on intrinsic membrane properties of hippocampal pyramidal neurons from young rats (postnatal day 15-20). Intracellular recordings of CA1 and CA3 pyramidal neurons from Flurothyl-treated and control rats revealed no significant differences in resting membrane potential, input resistance, membrane time constant, and action potential characteristics. In CA1 pyramidal cells from Flurothyl-treated rats, the spike frequency adaptation and afterhyperpolarizing potential following a spike train were markedly reduced when compared with controls. In contrast, no significant alterations in the firing properties of CA3 pyramidal neurons were found. It is concluded that neonatal seizures lead to persistent changes in intrinsic membrane properties of CA1 pyramidal neurons. These alterations are consistent with an increase in neuronal excitability and may contribute to the behavioral deficit and epileptogenic predisposition observed in rats that experienced repeated neonatal seizures.

  • Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study.
    Developmental Brain Research, 1999
    Co-Authors: Li-tung Huang, Carl E. Stafstrom, Maria Roberta Cilio, Diosely C. Silveira, Bridget K. Mccabe, Yoshimi Sogawa, Gregory L. Holmes
    Abstract:

    Previous studies have demonstrated that recurrent seizures during the neonatal period lead to permanent changes in seizure threshold and learning and memory. The pathophysiological mechanisms for these changes are not clear. To determine if neonatal seizures cause changes in hippocampal excitability or inhibition, we subjected rats to 50 Flurothyl-induced seizures during the first 10 days of life (five seizures per day). When the rats were adults, we examined seizure threshold using Flurothyl inhalation, and learning and memory in the water maze. In separate groups of animals, we evaluated in vivo paired-pulse facilitation and inhibition in either CA1 with stimulation of the Schaffer collaterals or dentate gyrus with stimulation of the perforant path. Following these studies, the animals were sacrificed and the brains evaluated for mossy fiber sprouting with the Timm stain. Compared to control animals, rats with 50 Flurothyl seizures had a reduced seizure threshold, impaired learning and memory in the water maze, and sprouting of mossy fibers in the CA3 pyramidal cell layer and molecular layer of the dentate gyrus. No significant differences in impaired paired-pulse inhibition was noted between the Flurothyl-treated and control rats. This study demonstrates that recurrent neonatal seizures result in changes of neuronal connectivity and alterations in seizure susceptibility, learning and memory. However, the degree of impairment following 50 seizures was modest, demonstrating that the immature brain is remarkably resilient to seizure-induced damage.

  • Effects of neonatal seizures on subsequent seizure-induced brain injury
    Neurology, 1999
    Co-Authors: Regula Schmid, Pushpa Tandon, Carl E. Stafstrom, Gregory L. Holmes
    Abstract:

    Background: Although seizures are very common in neonates and are often the harbinger of poor neurologic outcome, there is controversy regarding the degree of brain damage induced by seizures during early development. Here, we evaluated the effect of neonatal seizures on subsequent brain injury induced by status epilepticus. Methods: Twenty-five seizures were induced by the inhalant Flurothyl in neonatal rats during the first 5 days of life. Flurothyl reliably produced generalized seizures with concomitant electroencephalographic changes and a low mortality rate. During adolescence or early adulthood, animals were subjected to status epilepticus using either kainic acid or perforant path stimulation. Results: Although Flurothyl-induced neonatal seizures did not cause cell death, animals that had neonatal seizures had significantly more severe brain injury after both kainic acid and perforant path stimulation than did animals without a history of neonatal seizures. Conclusions: Neonatal seizures increase the susceptibility of the developing brain to subsequent seizure-induced injury.

Solomon L. Moshé - One of the best experts on this subject based on the ideXlab platform.

  • Effect of ganaxolone on Flurothyl seizures in developing rats.
    Epilepsia, 2000
    Co-Authors: Soňa Liptáková, Libor Velíšek, Jana Velíšková, Solomon L. Moshé
    Abstract:

    Summary: Purpose: To determine the effects of a newly synthesized epalon, ganaxolone (GNX), on primarily generalized seizures in rats of various ages during development. Epalons are classified as neuroactive steroids that interact at unique site of the GABAA receptor-Cl− channel complex in the central nervous system. Methods: Sprague-Dawley male rats were used at 9, 15, 30, and 60 postnatal days (PN). GNX dissolved in 2-hydroxypropyl-β-cyclodextrine was administered intraperitoneally in different doses at various time points before Flurothyl testing. The incidence and threshold of clonic and tonic-clonic Flurothyl seizures were evaluated. Behavioral changes were also assessed. Results: In all age groups, the effects of GNX were dose dependent and more prominent 10 min after its administration. In PN 60 and PN 30 rats, GNX had dose-dependent anticon-vulsant effects; tonic-clonic seizures were more sensitive to GNX treatment than clonic seizures. In PN 15 and PN 9 rats, GNX demonstrated dose- and time-dependent anticonvulsant effects against both types of Flurothyl-induced seizures. GNX was more effective in PN 15 rats than in other age groups, but at doses that altered motor behavior. Conclusions: GNX has anticonvulsant effects against Flurothyl-induced seizures in all age groups tested. Its effects are more prominent in the two younger age groups, especially in PN 15 rats, but are associated with motor side effects.

  • effects of mk 801 and phenytoin on Flurothyl induced seizures during development
    Epilepsia, 1995
    Co-Authors: Libor Velíšek, Jana Velíšková, Yael Ptachewich, Shlomo Shinnar, Solomon L. Moshé
    Abstract:

    We determined the effects of the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 (0.05, 0.1, and 0.5 mg/kg intraperitoneally, i.p.) and phenytoin (PHT, 5, 10, and 20 mg/kg i.p.) on Flurothyl-induced clonic and tonic-clonic seizures in 9-, 15-, 30-, and 60-day-old male rats. Both agents had seizure-, age-, and dose-specific effects. The highest dose of MK-801 was anticonvulsant against clonic Flurothyl-induced seizures only in 9- and 60-day-old rats, but suppressed tonic-clonic seizures in all ages. The lowest dose of MK-801 (0.05 mg/kg) produced significant anticonvulsant effects only in 15 day old rats. PHT did not have any effect on clonic seizures throughout development. Both doses of PHT (10 and 20 mg/kg) were anticonvulsant against tonic-clonic seizures in adult rats but not in any other age group. The results indicate that NMDA receptors play an important role in tonic-clonic Flurothyl-induced seizures throughout development (especially in 15-day-old rats) and that the anticonvulsant effects of PHT may vary at different stages of brain development.

  • Prenatal exposure to aspartame and seizure susceptibility
    Journal of Epilepsy, 1995
    Co-Authors: Ellen F. Sperber, Solomon L. Moshé, Diana L. Dow-edwards
    Abstract:

    Abstract Aspartame has been reported to be proconvulsant in rats and mice. To determine whether gestational exposure to aspartame alters susceptibility to Flurothyl-induced seizures in offspring, we administered either 500 or 750 mg/kg aspartame to pregnant guinea pigs throughout pregnancy. The offspring were exposed to Flurothyl at age 30 days to determine the threshold for clonic and tonic seizures. We also examined offspring from a gavaged control group and a nontreated control group. There were no statistically significant differences in either clonic or tonic seizure thresholds among all groups. Therefore, aspartame administration throughout pregnancy in guinea pigs had no epileptogenic potential in the Flurothyl model.

  • Effects of MK‐801 and Phenytoin on Flurothyl‐Induced Seizures During Development
    Epilepsia, 1995
    Co-Authors: Libor Velíšek, Jana Velíšková, Yael Ptachewich, Shlomo Shinnar, Solomon L. Moshé
    Abstract:

    We determined the effects of the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 (0.05, 0.1, and 0.5 mg/kg intraperitoneally, i.p.) and phenytoin (PHT, 5, 10, and 20 mg/kg i.p.) on Flurothyl-induced clonic and tonic-clonic seizures in 9-, 15-, 30-, and 60-day-old male rats. Both agents had seizure-, age-, and dose-specific effects. The highest dose of MK-801 was anticonvulsant against clonic Flurothyl-induced seizures only in 9- and 60-day-old rats, but suppressed tonic-clonic seizures in all ages. The lowest dose of MK-801 (0.05 mg/kg) produced significant anticonvulsant effects only in 15 day old rats. PHT did not have any effect on clonic seizures throughout development. Both doses of PHT (10 and 20 mg/kg) were anticonvulsant against tonic-clonic seizures in adult rats but not in any other age group. The results indicate that NMDA receptors play an important role in tonic-clonic Flurothyl-induced seizures throughout development (especially in 15-day-old rats) and that the anticonvulsant effects of PHT may vary at different stages of brain development.

  • The proconvulsant effect of nigral infusions of THIP on Flurothyl-induced seizures in rat pups.
    Brain research. Developmental brain research, 1992
    Co-Authors: Douglas S. Garant, Ellen F. Sperber, Solomon L. Moshé
    Abstract:

    Abstract The substantia nigra γ-aminobutyric acid (GABA) system is crucial for seizure control. Our previous work indicates that in 16-day-old rat pups, nigral administration of the GABA A receptor agonist muscimol facilities Flurothyl-induced seizures, whereas it suppresses seizures in adult rats. To determine whether the proconvulsant effect of muscimol in rat pups may be mediated by nigral GABA A receptors, in the present study we applied a selective GABA A receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Bilateral nigral infusions of THIP (500 or 700 ng) significantly decreased the thresholds for Flurothyl seizures in a dose-dependent fashion. Doses of 350 ng or less did not significantly modify the susceptibility to seizures. An anticonvulsant action of THIP could not be detected at any dose. Administration of an effective THIP dose (500 ng) 2 mm dorsal to the SNR had no influence on seizures. These findings suggest that in rat pups the proconvulsant effect of nigral GABA A receptor agonists may be attributed to unique pharmacologic characteristics of GABA A receptors during development.

Dominick Papandrea - One of the best experts on this subject based on the ideXlab platform.

  • spatiotemporal differences in the c fos pathway between c57bl 6j and dba 2j mice following Flurothyl induced seizures a dissociation of hippocampal fos from seizure activity
    Epilepsy Research, 2015
    Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Tara M. Anderson, Bruce J. Herron, Russell J. Ferland, Karina Tuz, Sachidhanand Jayakumar
    Abstract:

    Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final Flurothyl rechallenge. Two brain regions, the hippocampus and ventromedial nucleus of the hypothalamus (VMH), had significantly different Fos expression profiles following seizures. Fos expression was highly robust in B6 hippocampus following one seizure and remained elevated following multiple seizures. Conversely, there was an absence of Fos (and phospho-Erk) expression in D2 hippocampus following one generalized seizure that increased with multiple seizures. This lack of Fos expression occurred despite intracranial electroencephalographic recordings indicating that the D2 hippocampus propagated ictal discharge during the first Flurothyl seizure suggesting a dissociation of seizure discharge from Fos and phospho-Erk expression. Global transcriptional analysis confirmed a dysregulation of the c-fos pathway in D2 mice following 1 seizure. Moreover, global analysis of RNA expression differences between B6 and D2 hippocampus revealed a unique pattern of transcripts that were co-regulated with Fos in D2 hippocampus following 1 seizure. These expression differences could, in part, account for D2's seizure susceptibility phenotype. Following 8 seizures, a 28 day rest period, and a final Flurothyl rechallenge, ∼85% of B6 mice develop a more complex seizure phenotype consisting of a clonic-forebrain seizure that uninterruptedly progresses into a brainstem seizure. This seizure phenotype in B6 mice is highly correlated with bilateral Fos expression in the VMH and was not observed in D2 mice, which always express clonic-forebrain seizures upon Flurothyl retest. Overall, these results illustrate specific differences in protein and RNA expression in different inbred strains following seizures that precede the reorganizational events that affect seizure susceptibility and changes in seizure semiology over time.

  • Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following Flurothyl-induced seizures: a dissociation of hippocampal Fos from seizure activity
    Epilepsy research, 2014
    Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Tara M. Anderson, Bruce J. Herron, Karina Tuz, Sachidhanand Jayakumar, Russell J. Ferland
    Abstract:

    Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final Flurothyl rechallenge. Two brain regions, the hippocampus and ventromedial nucleus of the hypothalamus (VMH), had significantly different Fos expression profiles following seizures. Fos expression was highly robust in B6 hippocampus following one seizure and remained elevated following multiple seizures. Conversely, there was an absence of Fos (and phospho-Erk) expression in D2 hippocampus following one generalized seizure that increased with multiple seizures. This lack of Fos expression occurred despite intracranial electroencephalographic recordings indicating that the D2 hippocampus propagated ictal discharge during the first Flurothyl seizure suggesting a dissociation of seizure discharge from Fos and phospho-Erk expression. Global transcriptional analysis confirmed a dysregulation of the c-fos pathway in D2 mice following 1 seizure. Moreover, global analysis of RNA expression differences between B6 and D2 hippocampus revealed a unique pattern of transcripts that were co-regulated with Fos in D2 hippocampus following 1 seizure. These expression differences could, in part, account for D2's seizure susceptibility phenotype. Following 8 seizures, a 28 day rest period, and a final Flurothyl rechallenge, ∼85% of B6 mice develop a more complex seizure phenotype consisting of a clonic-forebrain seizure that uninterruptedly progresses into a brainstem seizure. This seizure phenotype in B6 mice is highly correlated with bilateral Fos expression in the VMH and was not observed in D2 mice, which always express clonic-forebrain seizures upon Flurothyl retest. Overall, these results illustrate specific differences in protein and RNA expression in different inbred strains following seizures that precede the reorganizational events that affect seizure susceptibility and changes in seizure semiology over time.

  • Segregation of Seizure Traits in C57 Black Mouse Substrains Using the Repeated-Flurothyl Model
    PloS one, 2014
    Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Bruce J. Herron, Russell J. Ferland
    Abstract:

    Identifying the genetic basis of epilepsy in humans is difficult due to its complexity, thereby underlying the need for preclinical models with specific aspects of seizure susceptibility that are tractable to genetic analyses. In the repeated-Flurothyl model, mice are given 8 Flurothyl-induced seizures, once per day (the induction phase), followed by a 28-day rest period (incubation phase) and final Flurothyl challenge. This paradigm allows for the tracking of multiple phenotypes including: initial generalized seizure threshold, decreases in generalized seizure threshold with repeated Flurothyl exposures, and changes in the complexity of seizures over time. Given the responses we previously reported in C57BL/6J mice, we analyzed substrains of the C57BL lineage to determine if any of these phenotypes segregated in these substrains. We found that the generalized seizure thresholds of C57BL/10SNJ and C57BL/10J mice were similar to C57BL/6J mice, whereas C57BL/6NJ and C57BLKS/J mice showed lower generalized seizure thresholds. In addition, C57BL/6J mice had the largest decreases in generalized seizure thresholds over the induction phase, while the other substrains were less pronounced. Notably, we observed only clonic seizures during the induction phase in all substrains, but when rechallenged with Flurothyl after a 28-day incubation phase, ∼80% of C57BL/6J and 25% of C57BL/10SNJ and C57BL/10J mice expressed more complex seizures with tonic manifestations with none of the C57BL/6NJ and C57BLKS/J mice having complex seizures with tonic manifestations. These data indicate that while closely related, the C57BL lineage has significant diversity in aspects of epilepsy that are genetically controlled. Such differences further highlight the importance of genetic background in assessing the effects of targeted deletions of genes in preclinical epilepsy models.

  • C57BL substrain differences in generalized seizure thresholds.
    2014
    Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Bruce J. Herron, Russell J. Ferland
    Abstract:

    The latency to a generalized seizure (generalized seizure threshold (GST)) on each seizure trial was determined for 5 C57BL substrains (n = 12 mice/substrain: 10SNJ, 10J, 6J, 6NJ, and KSJ) by exposure to 10% Flurothyl during eight induction trials followed by a 28-day rest period and a single Flurothyl retest. The baseline GST of 10SNJ mice and 10J mice were similar to that of 6J mice, whereas 6NJ and KSJ mice have significantly lower initial GST (P

  • Flurothyl-induced seizure behaviors in C57BL substrains following 8 seizures, a 28-day incubation phase, and a final Flurothyl challenge.
    2014
    Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Bruce J. Herron, Russell J. Ferland
    Abstract:

    While none of the 6NJ and KSJ mice expressed a more complex forebrain→brainstem seizure on Flurothyl rechallenge, 25% of 10SNJ mice, 25% of 10J mice, and ∼80% of 6J mice did express a more complex forebrain→brainstem seizure. This demonstrates that the evolution of more complex seizures, following exposure to the repeated-Flurothyl model, is controlled by alleles in the B6 genetic background. Chi-square analysis demonstrated a significant difference between substrains (Χ4 = 28.45; P

Libor Velíšek - One of the best experts on this subject based on the ideXlab platform.

  • Developmental decrease in parvalbumin-positive neurons precedes increase in Flurothyl-induced seizure susceptibility in the Brd2+/- mouse model of juvenile myoclonic epilepsy.
    Epilepsia, 2020
    Co-Authors: Emily Mccarthy, Jana Velíšková, Faariah Shakil, Patrick Saint Ange, Emily Cameron, James Miller, Shilpa Pathak, David A. Greenberg, Libor Velíšek
    Abstract:

    OBJECTIVE BRD2 is a human gene repeatedly linked to and associated with juvenile myoclonic epilepsy (JME). Here, we define the developmental stage when increased seizure susceptibility first manifests in heterozygous Brd2+/- mice, an animal model of JME. We wanted to determine (1) whether seizure susceptibility correlates with the proven decrease of γ-aminobutyric acidergic (GABAergic) neuron numbers and (2) whether the seizure phenotype can be affected by sex hormones. METHODS Heterozygous (Brd2+/-) and wild-type (wt) mice of both sexes were tested for Flurothyl-induced seizure susceptibility at postnatal day 15 (P15; wt, n = 13; Brd2+/-, n = 20), at P30 (wt, n = 20; Brd2+/-, n = 20), and in adulthood (5-6 months of age; wt, n = 10; Brd2+/-, n = 12). We measured latency to clonic and tonic-clonic seizure onset (Flurothyl threshold). We also compared relative density of parvalbumin-positive (PVA+) and GAD67+ GABA neurons in the striatum and primary motor (M1) neocortex of P15 (n = 6-13 mice per subgroup) and P30 (n = 7-10 mice per subgroup) mice. Additional neonatal Brd2+/- mice were injected with testosterone propionate (females) or formestane (males) and challenged with Flurothyl at P30. RESULTS P15 Brd2+/- mice showed no difference in seizure susceptibility compared to P15 wt mice. However, even at this early age, Brd2+/- mice showed fewer PVA+ neurons in the striatum and M1 neocortex. Compared to wt, the striatum in Brd2+/- mice showed an increased proportion of immature PVA+ neurons, with smaller cell bodies and limited dendritic arborization. P30 Brd2+/- mice displayed increased susceptibility to Flurothyl-induced clonic seizures compared to wt. Both genotype and sex strongly influenced the density of PVA+ neurons in the striatum. Susceptibility to clonic seizures remained increased in adult Brd2+/- mice, and additionally there was increased susceptibility to tonic-clonic seizures. In P30 females, neonatal testosterone reduced the number of Flurothyl-induced clonic seizures. SIGNIFICANCE A decrease in striatal PVA+ GABAergic neurons developmentally precedes the onset of increased seizure susceptibility and likely contributes to the expression of the syndrome.

  • Susceptibility of Brd2 heterozygous KO mice (+/-) and control littermates (+/+) to Flurothyl-induced seizures.
    2013
    Co-Authors: Libor Velíšek, Jana Velíšková, Enyuan Shang, Tamar Chachua, Stephania Macchiarulo, Giorgi Maglakelidze, Debra J. Wolgemuth, David A. Greenberg
    Abstract:

    Seizure threshold is depicted in µl of Flurothyl necessary to induce specific seizure type (Mean±S.E.M.). (A) In females, tonic-clonic seizures in Brd2+/- mice had significantly lower threshold than in Brd2+/+ littermate controls. (B) In males, clonic seizures in Brd2+/− mice had significantly lower threshold than in Brd2+/+ littermate controls.

  • correlation between extracellular glucose and seizure susceptibility in adult rats
    Annals of Neurology, 2003
    Co-Authors: Evan M Schwechter, Jana Velíšková, Libor Velíšek
    Abstract:

    In adult diabetic patients, periods of hyperglycemia may be associated with exacerbation of focal seizures. Our objective was to determine in the adult rats the correlation between seizure susceptibility and extracellular glucose concentration in two models of seizures. Male rats were injected with two doses of streptozocin (40mg/kg IP) on 2 consecutive days to induce diabetic hyperglycemia. Controls either received vehicle or were not injected. After 2 weeks, blood glucose concentration was measured, and the rats were subjected to Flurothyl seizure test. Another group of rats received glucose solution (20%, 5ml IP) 30 minutes before testing to induce nondiabetic hyperglycemia. Thresholds for Flurothyl-induced clonic and tonic-clonic seizures were determined. Finally, in vitro epileptiform activity was induced in the entorhinal cortex-hippocampal slices from naive rats by perfusing with magnesium-free medium with various glucose concentrations. In additional slices, paired-pulse paradigm was determined in the perforant path. Susceptibility to clonic and tonic-clonic Flurothyl-induced seizures positively correlated with blood glucose concentrations as the increased glucose concentration was associated with proconvulsant effects. Similarly, in the in vitro experiments, epileptiform activity was promoted by increased and suppressed by decreased glucose concentrations. Data indicate that, in the adult rats, high glucose concentrations are associated with proconvulsant effects.

  • Effect of ganaxolone on Flurothyl seizures in developing rats.
    Epilepsia, 2000
    Co-Authors: Soňa Liptáková, Libor Velíšek, Jana Velíšková, Solomon L. Moshé
    Abstract:

    Summary: Purpose: To determine the effects of a newly synthesized epalon, ganaxolone (GNX), on primarily generalized seizures in rats of various ages during development. Epalons are classified as neuroactive steroids that interact at unique site of the GABAA receptor-Cl− channel complex in the central nervous system. Methods: Sprague-Dawley male rats were used at 9, 15, 30, and 60 postnatal days (PN). GNX dissolved in 2-hydroxypropyl-β-cyclodextrine was administered intraperitoneally in different doses at various time points before Flurothyl testing. The incidence and threshold of clonic and tonic-clonic Flurothyl seizures were evaluated. Behavioral changes were also assessed. Results: In all age groups, the effects of GNX were dose dependent and more prominent 10 min after its administration. In PN 60 and PN 30 rats, GNX had dose-dependent anticon-vulsant effects; tonic-clonic seizures were more sensitive to GNX treatment than clonic seizures. In PN 15 and PN 9 rats, GNX demonstrated dose- and time-dependent anticonvulsant effects against both types of Flurothyl-induced seizures. GNX was more effective in PN 15 rats than in other age groups, but at doses that altered motor behavior. Conclusions: GNX has anticonvulsant effects against Flurothyl-induced seizures in all age groups tested. Its effects are more prominent in the two younger age groups, especially in PN 15 rats, but are associated with motor side effects.

  • Laboratory Research Effect of Ganaxolone on Flurothyl Seizures in Developing Rats
    2000
    Co-Authors: Libor Velíšek, Solomon L. Mosh
    Abstract:

    Summary: Purpose: To determine the effects of a newly synthesized epalon, ganaxolone (GNX), on primarily generalized seizures in rats of various ages during development. Epalons are classified as neuroactive steroids that interact at unique site of the GABA, receptor-CI- channel complex in the central nervous system. Methods: Sprague-Dawley male rats were used at 9, 15, 30, and 60 postnatal days (PN). GNX dissolved in 2-hydroxypropylP-cyclodextrine was administered intraperitoneally in different doses at various time points before Flurothyl testing. The incidence and threshold of clonic and tonic-clonic Flurothyl seizures were evaluated. Behavioral changes were also assessed. Results: In all age groups, the effects of GNX were dose dependent and more prominent 10 min after its administration. In PN 60 and PN 30 rats, GNX had dose-dependent anticonvulsant effects; tonic-clonic seizures were more sensitive to GNX treatment than clonic seizures. In PN 15 and PN 9 rats, GNX demonstrated dose- and time-dependent anticonvulsant effects against both types of Flurothyl-induced seizures. GNX was more effective in PN 15 rats than in other age groups, but at doses that altered motor behavior. Conclusions: GNX has anticonvulsant effects against Flurothylinduced seizures in all age groups tested. Its effects are more prominent in the two younger age groups, especially in PN 15 rats, but are associated with motor side effects. Key Wards: Ganaxolone-Seizures-Rats-Development-Flurothy I. Neurosteroids (also called neuroactive steroids) are steroid hormones that can be formed de novo in the central nervous system (CNS) (1). Neurosteroids can also be produced in brain tissues from the conversion of peripheral steroid hormones such as progesterone, deoxycorticosterone, and testosterone, which can cross the blood-brain barrier (2). Endogenous or synthetic neuroactive steroids' alter neuronal excitability by rapidly acting on the neuronal membrane within seconds to minutes