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Ronald A. Browning - One of the best experts on this subject based on the ideXlab platform.
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Localization of the serotonergic terminal fields modulating seizures in the Genetically Epilepsy-Prone Rat.
Epilepsy Research, 2007Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, John W. Dailey, Ronald A. BrowningAbstract:Summary Serotonin (5-HT) has been shown to exert antiepileptic effects in a variety of generalized convulsive seizure models, particularly the Genetically Epilepsy-Prone Rat (GEPR). The present study was designed to identify the region/site(s) where 5-HT exerts anticonvulsant effects in the GEPR-9, a model in which sound-evoked generalized tonic–clonic seizures (GTCS) are highly sensitive to manipulations in 5-HT concentRation. Because the 5-HT reuptake inhibitor, fluoxetine, was known to exert anticonvulsant effects in GEPR-9s via a 5-HT-dependent mechanism, we utilized selective regional 5-HT depletion in combination with systemic fluoxetine administRation to find the site where a 5-HT deficit would prevent the anticonvulsant action of fluoxetine. Widespread destruction of serotonergic terminal fields or regionally specific terminal field destruction was achieved using intracerebroventricular and more target specific infusions of 5,7-dihydroxytryptamine. The capacity of fluoxetine to suppress seizures in GEPR-9s following a loss of 5-HT was then examined. The present findings show the anticonvulsant action of fluoxetine is markedly attenuated following the loss of midbrain 5-HT, particularly in the region of the superior colliculus, while forebrain and spinal cord 5-HT do not appear to play a role in the action of fluoxetine. The importance of the deep layers of the SC was confirmed by demonstRating that direct microinfusion of fluoxetine into the SC can suppress seizures in Rats pretreated with the 5-HT 1A receptor antagonist pindolol.
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brainstem seizure severity regulates forebrain seizure expression in the audiogenic kindling model
Epilepsia, 2005Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: Although sound-induced (audiogenic) seizures in the Genetically Epilepsy-Prone Rat (GEPR) initially occur independent of the forebrain, repeated audiogenic seizures recruit forebrain seizure circuits in a process referred to as audiogenic kindling. In GEPR-3s, audiogenic kindling results in facial and forelimb (F&F) clonic seizures that are typical of forebrain seizures. However, in GEPR-9s, audiogenic kindling produces posttonic all-limb clonus not usually observed during forebrain seizures. We hypothesized that the more severe brainstem seizures of the GEPR-9 prevent the expression of F&F clonic seizures during audiogenic kindling. Therefore attenuation of audiogenic seizures during audiogenic kindling in GEPR-9s should allow F&F clonic seizures to be expressed. Likewise, intensifying audiogenic seizure severity in GEPR-3s should inhibit audiogenically kindled F&F clonic seizures. We have tested this hypothesis in the present study. Methods: Lesions of the superior colliculus or treatment with low-dose phenytoin were used to suppress audiogenic seizure severity in GEPR-9s. Depletion of brain serotonin was used to increase the seizure severity in GEPR-3s. All GEPRs were then subjected to audiogenic kindling. Behavioral and electrographic seizures were assessed. Results: Suppression of audiogenic seizure severity during audiogenic kindling in GEPR-9s increased the incidence forebrain seizure behavior. Kindled GEPR-9s that continued to display full tonic seizures did not exhibit forebrain convulsions, but did show posttonic clonus and forebrain seizure activity in the EEG. GEPR-3s chronically depleted of brain serotonin, along with displaying tonic brainstem seizures, tended to display less severe forebrain seizures during audiogenic kindling. Conclusions: These findings support the concept that severe brainstem seizures prevent the behavioral expression of forebrain seizures in audiogenically kindled GEPR-9s. It appears that the severe brainstem seizure of the GEPR-9 does not allow the forebrain seizure to manifest its typical behavioral concomitants despite electrographic evidence that spike–wave discharge is occurring in the forebrain.
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brainstem seizure severity regulates forebrain seizure expression in the audiogenic kindling model
Epilepsia, 2005Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: Although sound-induced (audiogenic) seizures in the Genetically Epilepsy-Prone Rat (GEPR) initially occur independent of the forebrain, repeated audiogenic seizures recruit forebrain seizure circuits in a process referred to as audiogenic kindling. In GEPR-3s, audiogenic kindling results in facial and forelimb (F&F) clonic seizures that are typical of forebrain seizures. However, in GEPR-9s, audiogenic kindling produces posttonic all-limb clonus not usually observed during forebrain seizures. We hypothesized that the more severe brainstem seizures of the GEPR-9 prevent the expression of F&F clonic seizures during audiogenic kindling. Therefore attenuation of audiogenic seizures during audiogenic kindling in GEPR-9s should allow F&F clonic seizures to be expressed. Likewise, intensifying audiogenic seizure severity in GEPR-3s should inhibit audiogenically kindled F&F clonic seizures. We have tested this hypothesis in the present study. Methods: Lesions of the superior colliculus or treatment with low-dose phenytoin were used to suppress audiogenic seizure severity in GEPR-9s. Depletion of brain serotonin was used to increase the seizure severity in GEPR-3s. All GEPRs were then subjected to audiogenic kindling. Behavioral and electrographic seizures were assessed. Results: Suppression of audiogenic seizure severity during audiogenic kindling in GEPR-9s increased the incidence forebrain seizure behavior. Kindled GEPR-9s that continued to display full tonic seizures did not exhibit forebrain convulsions, but did show posttonic clonus and forebrain seizure activity in the EEG. GEPR-3s chronically depleted of brain serotonin, along with displaying tonic brainstem seizures, tended to display less severe forebrain seizures during audiogenic kindling. Conclusions: These findings support the concept that severe brainstem seizures prevent the behavioral expression of forebrain seizures in audiogenically kindled GEPR-9s. It appears that the severe brainstem seizure of the GEPR-9 does not allow the forebrain seizure to manifest its typical behavioral concomitants despite electrographic evidence that spike–wave discharge is occurring in the forebrain.
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Role of the Superior Colliculus and the Intercollicular Nucleus in the Brainstem Seizure Circuitry of the Genetically Epilepsy-Prone Rat
Epilepsia, 2003Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: The neuronal network responsible for the convulsive behavior associated with sound-induced seizures in Genetically Epilepsy-Prone Rats (GEPRs) is believed to include the inferior colliculus and other brainstem structures such as the deep layers of the superior colliculus (DLSC), periaqueductal gray, and pontine reticular formation. However, previous studies also suggested that the DLSC and the nearby intercollicular nucleus (ICN) are part of a midbrain anticonvulsant zone capable of suppressing tonic convulsions when activated with bicuculline. Our aim in this study was to investigate the role of the superior colliculus (SC) and the ICN in generalized tonic–clonic seizures (GTCSs). Methods: Bilateral lesions of the SC and the ICN as well as bicuculline infusions into the ICN were used to assess the role of this dorsal midbrain region in brainstem seizures induced by sound stimulation in GEPR-9s and GEPR-3s. Results: Lesions of the SC markedly attenuated audiogenic seizure (AGS) severity by abolishing all behavioral components except the wild running. Lesions of the ICN significantly reduced seizure severity in GEPR-9s, but were somewhat less effective than SC lesions. Bicuculline infusion into the deep layers of the SC and/or the ICN produced audiogenic-like seizures in GEPR-9s. Conclusions: These findings support the hypothesis that the SC and ICN are important components of the brainstem seizure network, but suggest they are not necessary for the wild-running component of the seizure. The results further indicate that stimulation of the tectum facilitates GTCSs. Thus these findings suggest that the dorsal midbrain, when stimulated, is proconvulsant Rather than anticonvulsant regarding brainstem seizures in GEPRs.
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Morphological deficits in noradrenergic neurons in GEPR-9s stem from abnormalities in both the locus coeruleus and its target tissues.
Experimental Neurology, 1999Co-Authors: Jae Ryun Ryu, Phillip C Jobe, Ronald A. Browning, P K Mishra, John W. Dailey, Rich W Clough, Joseph C. Milbrandt, Dong Ook SeoAbstract:The epileptic condition of the Genetically Epilepsy-Prone Rat (GEPR) appears to be caused partially by deficiencies in the locus coeruleus (LC) innervation of the superior colliculus (SC). Previous studies provide quantitative documentation of noradrenergic morphological deficits in the modeRately epileptic GEPR-3. The present findings extend these studies by applying cell culture methodology to assessments of the severely epileptic GEPR-9. Our data show that total neurite length, the number of neurite branch points per cell, the cross-sectional area of cell bodies, and the cell perimeter are deficient in noradrenergic neurons in LC + SC cocultures derived exclusively from GEPR-9s compared to analogous cocultures obtained solely from nonepileptic control Rats. Partial restoRation of LC neuron morphology toward normal occurs when the GEPR-9 SC component of the coculture is replaced with nonepileptic control SC. Finally, when the GEPR-9 SC is cocultured with the control LC, a partial morphological deficit occurs in the otherwise normal noradrenergic neurons. However, the magnitude of this deficit is less than that observed in noradrenergic neurons of the GEPR-9 LC cocultured with the control SC. These data support the hypothesis that the developmental deficiencies of noradrenergic neurons of the GEPR-9 are derived from two sources, the LC and its target tissue, in this case, the SC. Also, intrinsic abnormalities of the LC appear to make a more pronounced contribution to the noradrenergic deficits than do those which reside in the SC.
Phillip C Jobe - One of the best experts on this subject based on the ideXlab platform.
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Localization of the serotonergic terminal fields modulating seizures in the Genetically Epilepsy-Prone Rat.
Epilepsy Research, 2007Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, John W. Dailey, Ronald A. BrowningAbstract:Summary Serotonin (5-HT) has been shown to exert antiepileptic effects in a variety of generalized convulsive seizure models, particularly the Genetically Epilepsy-Prone Rat (GEPR). The present study was designed to identify the region/site(s) where 5-HT exerts anticonvulsant effects in the GEPR-9, a model in which sound-evoked generalized tonic–clonic seizures (GTCS) are highly sensitive to manipulations in 5-HT concentRation. Because the 5-HT reuptake inhibitor, fluoxetine, was known to exert anticonvulsant effects in GEPR-9s via a 5-HT-dependent mechanism, we utilized selective regional 5-HT depletion in combination with systemic fluoxetine administRation to find the site where a 5-HT deficit would prevent the anticonvulsant action of fluoxetine. Widespread destruction of serotonergic terminal fields or regionally specific terminal field destruction was achieved using intracerebroventricular and more target specific infusions of 5,7-dihydroxytryptamine. The capacity of fluoxetine to suppress seizures in GEPR-9s following a loss of 5-HT was then examined. The present findings show the anticonvulsant action of fluoxetine is markedly attenuated following the loss of midbrain 5-HT, particularly in the region of the superior colliculus, while forebrain and spinal cord 5-HT do not appear to play a role in the action of fluoxetine. The importance of the deep layers of the SC was confirmed by demonstRating that direct microinfusion of fluoxetine into the SC can suppress seizures in Rats pretreated with the 5-HT 1A receptor antagonist pindolol.
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brainstem seizure severity regulates forebrain seizure expression in the audiogenic kindling model
Epilepsia, 2005Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: Although sound-induced (audiogenic) seizures in the Genetically Epilepsy-Prone Rat (GEPR) initially occur independent of the forebrain, repeated audiogenic seizures recruit forebrain seizure circuits in a process referred to as audiogenic kindling. In GEPR-3s, audiogenic kindling results in facial and forelimb (F&F) clonic seizures that are typical of forebrain seizures. However, in GEPR-9s, audiogenic kindling produces posttonic all-limb clonus not usually observed during forebrain seizures. We hypothesized that the more severe brainstem seizures of the GEPR-9 prevent the expression of F&F clonic seizures during audiogenic kindling. Therefore attenuation of audiogenic seizures during audiogenic kindling in GEPR-9s should allow F&F clonic seizures to be expressed. Likewise, intensifying audiogenic seizure severity in GEPR-3s should inhibit audiogenically kindled F&F clonic seizures. We have tested this hypothesis in the present study. Methods: Lesions of the superior colliculus or treatment with low-dose phenytoin were used to suppress audiogenic seizure severity in GEPR-9s. Depletion of brain serotonin was used to increase the seizure severity in GEPR-3s. All GEPRs were then subjected to audiogenic kindling. Behavioral and electrographic seizures were assessed. Results: Suppression of audiogenic seizure severity during audiogenic kindling in GEPR-9s increased the incidence forebrain seizure behavior. Kindled GEPR-9s that continued to display full tonic seizures did not exhibit forebrain convulsions, but did show posttonic clonus and forebrain seizure activity in the EEG. GEPR-3s chronically depleted of brain serotonin, along with displaying tonic brainstem seizures, tended to display less severe forebrain seizures during audiogenic kindling. Conclusions: These findings support the concept that severe brainstem seizures prevent the behavioral expression of forebrain seizures in audiogenically kindled GEPR-9s. It appears that the severe brainstem seizure of the GEPR-9 does not allow the forebrain seizure to manifest its typical behavioral concomitants despite electrographic evidence that spike–wave discharge is occurring in the forebrain.
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brainstem seizure severity regulates forebrain seizure expression in the audiogenic kindling model
Epilepsia, 2005Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: Although sound-induced (audiogenic) seizures in the Genetically Epilepsy-Prone Rat (GEPR) initially occur independent of the forebrain, repeated audiogenic seizures recruit forebrain seizure circuits in a process referred to as audiogenic kindling. In GEPR-3s, audiogenic kindling results in facial and forelimb (F&F) clonic seizures that are typical of forebrain seizures. However, in GEPR-9s, audiogenic kindling produces posttonic all-limb clonus not usually observed during forebrain seizures. We hypothesized that the more severe brainstem seizures of the GEPR-9 prevent the expression of F&F clonic seizures during audiogenic kindling. Therefore attenuation of audiogenic seizures during audiogenic kindling in GEPR-9s should allow F&F clonic seizures to be expressed. Likewise, intensifying audiogenic seizure severity in GEPR-3s should inhibit audiogenically kindled F&F clonic seizures. We have tested this hypothesis in the present study. Methods: Lesions of the superior colliculus or treatment with low-dose phenytoin were used to suppress audiogenic seizure severity in GEPR-9s. Depletion of brain serotonin was used to increase the seizure severity in GEPR-3s. All GEPRs were then subjected to audiogenic kindling. Behavioral and electrographic seizures were assessed. Results: Suppression of audiogenic seizure severity during audiogenic kindling in GEPR-9s increased the incidence forebrain seizure behavior. Kindled GEPR-9s that continued to display full tonic seizures did not exhibit forebrain convulsions, but did show posttonic clonus and forebrain seizure activity in the EEG. GEPR-3s chronically depleted of brain serotonin, along with displaying tonic brainstem seizures, tended to display less severe forebrain seizures during audiogenic kindling. Conclusions: These findings support the concept that severe brainstem seizures prevent the behavioral expression of forebrain seizures in audiogenically kindled GEPR-9s. It appears that the severe brainstem seizure of the GEPR-9 does not allow the forebrain seizure to manifest its typical behavioral concomitants despite electrographic evidence that spike–wave discharge is occurring in the forebrain.
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A comprehensive electrographic and behavioral analysis of generalized tonic-clonic seizures of GEPR-9s.
Brain Research, 2005Co-Authors: Márcio Flávio Dutra Moraes, Phillip C Jobe, P K Mishra, M. Chavali, Norberto Garcia-cairascoAbstract:Abstract This study records noise-free intracerebral EEG of the Genetically epilepsy prone Rat (GEPR-9), along with behavioral correlates, during a seizure on unanesthetized freely behaving unrestrained animals. The GEPR-9 exhibits acoustically triggered generalized tonic–clonic seizures, and often times the EEG, recorded with conventional techniques, has resulted in data with imbedded movement artifact. For noise-free video-EEG recordings, we used a previously developed system that consists of a head connector with a FET preamplifier and battery, signal conditioning device (5000x gain, 1 Hz–100 Hz filters), A/D converter and video/PC–PC/video computer boards for recording image data. Each animal was implanted with three monopolar/referential electrodes chosen among the following areas: cortex, inferior colliculus, reticular formation and caudal medulla. The video-EEG data were quite similar for all recorded animals: (1) basal desynchronized EEG before sound stimulus; (2) increase in EEG frequency after stimulus and before seizure onset; (3) high-amplitude polyspikes during massive myoclonic thrusts with or without a very fast running episode; (4) an electrodecremental response during tonic extension; (5) wave and spike complex during forelimb and hindlimb tonic rigidity and posttonic clonus; (6) low-amplitude EEG during postictal depression. Time sequenced spectral analysis also highlights the epileptiform EEG pattern during seizure with high reproducibility between animals. While testing seizure naive GEPR-9s, there was a clear evolution from modest epileptiform EEG activity on the first acoustic stimulation to progressively higher amplitude, duRation and frequency epileptiform EEG activity throughout seizure repetition.
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Role of the Superior Colliculus and the Intercollicular Nucleus in the Brainstem Seizure Circuitry of the Genetically Epilepsy-Prone Rat
Epilepsia, 2003Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: The neuronal network responsible for the convulsive behavior associated with sound-induced seizures in Genetically Epilepsy-Prone Rats (GEPRs) is believed to include the inferior colliculus and other brainstem structures such as the deep layers of the superior colliculus (DLSC), periaqueductal gray, and pontine reticular formation. However, previous studies also suggested that the DLSC and the nearby intercollicular nucleus (ICN) are part of a midbrain anticonvulsant zone capable of suppressing tonic convulsions when activated with bicuculline. Our aim in this study was to investigate the role of the superior colliculus (SC) and the ICN in generalized tonic–clonic seizures (GTCSs). Methods: Bilateral lesions of the SC and the ICN as well as bicuculline infusions into the ICN were used to assess the role of this dorsal midbrain region in brainstem seizures induced by sound stimulation in GEPR-9s and GEPR-3s. Results: Lesions of the SC markedly attenuated audiogenic seizure (AGS) severity by abolishing all behavioral components except the wild running. Lesions of the ICN significantly reduced seizure severity in GEPR-9s, but were somewhat less effective than SC lesions. Bicuculline infusion into the deep layers of the SC and/or the ICN produced audiogenic-like seizures in GEPR-9s. Conclusions: These findings support the hypothesis that the SC and ICN are important components of the brainstem seizure network, but suggest they are not necessary for the wild-running component of the seizure. The results further indicate that stimulation of the tectum facilitates GTCSs. Thus these findings suggest that the dorsal midbrain, when stimulated, is proconvulsant Rather than anticonvulsant regarding brainstem seizures in GEPRs.
Carl L Faingold - One of the best experts on this subject based on the ideXlab platform.
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Drugs for Control of Epilepsy:: Actions on Neuronal Networks Involved in Seizure Disorders
2019Co-Authors: Carl L Faingold, Gerhard H. FrommAbstract:Neuronal Networks, Epilepsy and the Action of Antiepileptic Drugs (Carl L. Faingold). Overview of Neurotransmission: Relationship to the Action of Antiepileptic Drugs (Ronald A. Browning). Overview of Ion Channels, Anticonvulsant Drugs and Seizures (Carl L. Faingold). Overview of Actions of Antiepileptic Drugs on Repetitive Neuronal Firing (M. Steven Evans). Brain Slice Model of Epilepsy: Neuronal Networks and Actions of Antiepileptic Drugs (Suzanne Clark and Wilkie A. Wilson). Cobalt-Induced Focal Seizures: Neuronal Networks and Actions of Antiepileptic Drugs (Charles R. Craig and Brenda K. Colasanti). Convulsant-Induced Neocortical Epilepsy: Neuronal Networks and Anticonvulsant Actions In Vivo (Allen B. Chatt and John S. Ebersole). Kindling: Amygdaloid Neuronal Networks and Actions of Convulsant and Antiepileptic Drugs (Larry G. Stark). The Electroshock Model, Neural Networks and Antiepileptic Drugs (Ronald A. Browning). Neuronal Networks in Convulsant Drug-Induced Seizures (C arl L. Faingold and Awais Riaz). Genetically Epilepsy-Prone Rats: Actions of Antiepileptic Drugs and Monoaminergic Neurotransmitters (Phillip C. Jobe, Pravin K. Mishra and John W. Dailey). The Genetically Epilepsy-Prone Rat: Neuronal Networks and Actions of Amino Acid Neurotransmitters (Carl L. Faingold and Dean K. Naritoku). The Epileptic Gerbil: Neuronal Networks and Actions of Antiepileptic Drugs (Wolfgang L scher). The Epileptic Baboon: Hypothetical Neuronal Networks and Actions of Anticonvulsant Drugs (Christian Menini, Carmen Silva-BarRat and Robert Naquet). Classification of the Epilepsies (Henri Gastaut, and Benjamin G. Zifkin). Overview of the Pharmacokinetics of Antiepileptic Drugs (Henn Kutt). Overview of the Biotransformation of Anticonvulsant Drugs (C. Dean Withrow). Antiepileptic Drug Interactions: An Overview (Ilo E. Leppik). Antiepileptic Drug Toxicity: An Overview (Ilo Leppik). Antiepileptic Actions of Hydantoins (Ronald E. Browning and Carl L. Faingold). Antiep ileptic Actions of Carbamazepine (Gerhard H. Fromm). Antiepileptic Actions of BarbituRates (Maharaj K. Ticku and Shrinivas K. Kulkarni). Antiepileptic Actions of Valproate (Gerhard H. Fromm). Antiepileptic Actions of Benzodiazepines (Richard W. Olsen). Antiepileptic Actions of Ethosuximide (Gerhard H. Fromm). Anticonvulsant Drugs with New Mechanisms of Action (B.S. Meldrum). Antiepileptic Drugs Useful in the Treatment of Tonic-Clonic and Partial Epilepsy (Gerhard H. Fromm). Antiepileptic Drugs Useful in the Treatment of Absence Seizures (Gerhard H. Fromm). Antiepileptic Drugs Useful in Status Epilepticus (Daniel H. Lowenstein and Roger P. Simon). Index.
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Seizure susceptibility is associated with altered protein expression of voltage-gated calcium channel subunits in inferior colliculus neurons of the Genetically Epilepsy-Prone Rat
Brain Research, 2010Co-Authors: Prosper N'gouemo, Robert P. Yasuda, Carl L FaingoldAbstract:Abstract The inferior colliculus (IC) is the consensus site for seizure initiation in the Genetically Epilepsy-Prone Rat (GEPR). We have previously reported that the current density of high threshold voltage-activated (HVA) calcium (Ca2+) channels was markedly enhanced in IC neurons of the GEPR-3 (modeRate seizure severity substrain of the GEPR). The present study examines whether subunit protein levels of HVA Ca2+ channels are altered in IC neurons that exhibit enhanced Ca2+ current density. Quantification shows that the levels of protein expression of the Ca2+ channel pore-forming α1D (L-type) and α1E subunits (R-type) were significantly increased in IC neurons of seizure-naive GEPR-3s (SN-GEPR-3s) compared to control Sprague–Dawley (SD) Rats. Significant increases and decreases in the levels of protein expression of Ca2+ channel regulatory β3 and α2δ subunits occurred in IC neurons of SN-GEPR-3s compared to control SD Rats, respectively. No changes occurred in the protein expression of Ca2+ channel pore-forming α1A (P/Q-type), α1B (N-type) and α1C (L-type) subunits in IC neurons of SN-GEPR-3s compared to control SD Rats. A single seizure selectively enhanced protein expression of Ca2+ channel α1A subunits in IC neurons of GEPR-3s. Thus, up-regulation of Ca2+ channel α1D and α1E subunits may represent the molecular mechanisms for the enhanced current density of L- and R-type of HVA Ca2+ channels in IC neurons of the GEPR, and may contribute to the genetic basis of their enhanced seizure susceptibility. The up-regulation of Ca2+ channel α1A subunits induced by seizures may contribute to the increasing IC neuronal excitability that results from repetitive seizures in the GEPR.
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Calcium channel dysfunction in inferior colliculus neurons of the Genetically Epilepsy-Prone Rat
Neuropharmacology, 2009Co-Authors: Prosper N'gouemo, Carl L Faingold, Martin MoradAbstract:Abstract Voltage-gated calcium (Ca2+) channels are thought to play an important role in epileptogenesis and seizure geneRation. Here, using the whole cell configuRation of patch-clamp techniques, we report on the modifications of biophysical and pharmacological properties of high threshold voltage-activated Ca2+ channel currents in inferior colliculus (IC) neurons of the Genetically Epilepsy-Prone Rats (GEPR-3s). Ca2+ channel currents were measured by depolarizing pulses from a holding potential of −80 mV using barium (Ba2+) as the charge carrier. We found that the current density of high threshold voltage-activated Ca2+ channels was significantly larger in IC neurons of seizure-naive GEPR-3s compared to control Sprague–Dawley Rats, and that seizure episodes further enhanced the current density in the GEPR-3s. The increased current density was reflected by both a −20 mV shifts in channel activation and a 25% increase in the non-inactivating fraction of channels in seizure-naive GEPR-3s. Such changes were reduced by seizure episodes in the GEPR-3s. Pharmacological analysis of the current density suggests that upregulation of L-, N- and R-type of Ca2+ channels may contribute to IC neuronal hyperexcitability that leads to seizure susceptibility in the GEPR-3s.
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Protein expression of small conductance calcium-activated potassium channels is altered in inferior colliculus neurons of the Genetically Epilepsy-Prone Rat.
Brain Research, 2009Co-Authors: Prosper N'gouemo, Robert P. Yasuda, Carl L FaingoldAbstract:Abstract The Genetically Epilepsy-Prone Rat (GEPR) exhibits inherited predisposition to sound stimuli-induced generalized tonic-clonic seizures (audiogenic reflex seizures) and is a valid model to study the physiopathology of epilepsy. In this model, the inferior colliculus (IC) exhibits enhanced neuronal firing that is critical in the initiation of reflex audiogenic seizures. The mechanisms underlying IC neuronal hyperexcitability that leads to seizure susceptibility are not as yet fully understood. The present report shows that the levels of protein expression of SK1 and SK3 subtypes of the small conductance Ca 2+ -activated K + channels were significantly decreased, while SK2 channel proteins were increased in IC neurons of seizure-naive GEPR-3s (SN-GEPR-3), as compared to control Sprague-Dawley Rats. No significant change was found in the expression of BK channel proteins in IC neurons of SN-GEPR-3s. Single episode of reflex audiogenic seizures in the GEPR-3s did not significantly alter the protein expression of SK1–3 and BK channels in IC neurons compared to SN-GEPR-3s. Thus, downregulation of SK1 and SK3 channels and upregulation of SK2 channels provide direct evidence that these Ca 2+ -activated K + channels play important roles in IC neuronal hyperexcitability that leads to inherited seizure susceptibility in the GEPR.
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Neuronal networks in the Genetically Epilepsy-Prone Rat.
Advances in neurology, 1999Co-Authors: Carl L FaingoldAbstract:It is now possible to develop a dynamic neuronal network model for generalized convulsive seizures because of in vivo data recently obtained in a naturally occurring epilepsy model--the Genetically Epilepsy-Prone Rats (GEPR-9s). GEPR-9s exhibit audiogenic seizures (AGS) that consist of a sequence of discrete behavioral phases (i.e., wild running, clonus-tonus, and post-ictal depression). The neuronal firing changes in most nuclei implicated in the network during each phase of AGS in behaving GEPR-9s have been examined. The inferior colliculus is critical in AGS initiation, because extensive firing increases in inferior colliculus are observed preceding seizure initiation. The deep layers of superior colliculus (DLSC) are crucial to wild running, based on the emergence of tonic firing of DLSC neurons just preceding this phase. The pontine reticular nucleus (PRF) and periaqueductal gray (PAG) are critical to the clonic-tonic phase, because tonic firing patterns appear in these neurons just prior to this phase. During post-ictal depression all areas except the PRF are quiescent. These temporal relationships suggest that each nucleus plays a specific hierarchic role in each discrete convulsive behavior. Generalized tonic-clonic seizure behavior observed in human epilepsy, in GEPR-9s, and in other seizure models is likely to involve similar neuronal network components. The neurotransmitter mechanisms subserving the abnormal neuronal responses in the GEPR-9 neuronal network involve an increased availability of glutamate and a decrease in the effectiveness of gamma-aminobutyric acid (GABA) in many brain regions. Focal modification of the effects of GABA, glutamate, norepinephrine, or serotonin also modulates the nuclei of the network differentially. Together, these data reveal the anatomic, neurotransmitter, and neurophysiologic mechanisms of the neuronal network hierarchy in GEPR-9s, which is currently the most completely developed of any generalized convulsive model. Differential effects of anticonvulsants on the AGS phases and concomitant differential modifications of neuronal firing are observed on neurons in these network nuclei. With nearly complete identification of the network nuclei, the differential effects of these anticonvulsant drugs on different aspects of neuronal firing in different brain sites indicate that this experimental approach can likely identify the most sensitive therapeutic target for these agents. This concept is potentially vital to developing the most selective treatment of different convulsive behaviors occurring in human epilepsy. The neuronal network for AGS does not require brain structures rostral to the midbrain for seizure expression. However, the forebrain is recruited into an expanded seizure network through AGS repetition ("kindling"), resulting in prolonged AGS, post-tonic clonus, and epileptiform electrographic cortical abnormalities. AGS kindling produces network expansion into medial geniculate body (MGB) and amygdala and involves neuronal firing increases in MGB.
Michelle A Merrill - One of the best experts on this subject based on the ideXlab platform.
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Localization of the serotonergic terminal fields modulating seizures in the Genetically Epilepsy-Prone Rat.
Epilepsy Research, 2007Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, John W. Dailey, Ronald A. BrowningAbstract:Summary Serotonin (5-HT) has been shown to exert antiepileptic effects in a variety of generalized convulsive seizure models, particularly the Genetically Epilepsy-Prone Rat (GEPR). The present study was designed to identify the region/site(s) where 5-HT exerts anticonvulsant effects in the GEPR-9, a model in which sound-evoked generalized tonic–clonic seizures (GTCS) are highly sensitive to manipulations in 5-HT concentRation. Because the 5-HT reuptake inhibitor, fluoxetine, was known to exert anticonvulsant effects in GEPR-9s via a 5-HT-dependent mechanism, we utilized selective regional 5-HT depletion in combination with systemic fluoxetine administRation to find the site where a 5-HT deficit would prevent the anticonvulsant action of fluoxetine. Widespread destruction of serotonergic terminal fields or regionally specific terminal field destruction was achieved using intracerebroventricular and more target specific infusions of 5,7-dihydroxytryptamine. The capacity of fluoxetine to suppress seizures in GEPR-9s following a loss of 5-HT was then examined. The present findings show the anticonvulsant action of fluoxetine is markedly attenuated following the loss of midbrain 5-HT, particularly in the region of the superior colliculus, while forebrain and spinal cord 5-HT do not appear to play a role in the action of fluoxetine. The importance of the deep layers of the SC was confirmed by demonstRating that direct microinfusion of fluoxetine into the SC can suppress seizures in Rats pretreated with the 5-HT 1A receptor antagonist pindolol.
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brainstem seizure severity regulates forebrain seizure expression in the audiogenic kindling model
Epilepsia, 2005Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: Although sound-induced (audiogenic) seizures in the Genetically Epilepsy-Prone Rat (GEPR) initially occur independent of the forebrain, repeated audiogenic seizures recruit forebrain seizure circuits in a process referred to as audiogenic kindling. In GEPR-3s, audiogenic kindling results in facial and forelimb (F&F) clonic seizures that are typical of forebrain seizures. However, in GEPR-9s, audiogenic kindling produces posttonic all-limb clonus not usually observed during forebrain seizures. We hypothesized that the more severe brainstem seizures of the GEPR-9 prevent the expression of F&F clonic seizures during audiogenic kindling. Therefore attenuation of audiogenic seizures during audiogenic kindling in GEPR-9s should allow F&F clonic seizures to be expressed. Likewise, intensifying audiogenic seizure severity in GEPR-3s should inhibit audiogenically kindled F&F clonic seizures. We have tested this hypothesis in the present study. Methods: Lesions of the superior colliculus or treatment with low-dose phenytoin were used to suppress audiogenic seizure severity in GEPR-9s. Depletion of brain serotonin was used to increase the seizure severity in GEPR-3s. All GEPRs were then subjected to audiogenic kindling. Behavioral and electrographic seizures were assessed. Results: Suppression of audiogenic seizure severity during audiogenic kindling in GEPR-9s increased the incidence forebrain seizure behavior. Kindled GEPR-9s that continued to display full tonic seizures did not exhibit forebrain convulsions, but did show posttonic clonus and forebrain seizure activity in the EEG. GEPR-3s chronically depleted of brain serotonin, along with displaying tonic brainstem seizures, tended to display less severe forebrain seizures during audiogenic kindling. Conclusions: These findings support the concept that severe brainstem seizures prevent the behavioral expression of forebrain seizures in audiogenically kindled GEPR-9s. It appears that the severe brainstem seizure of the GEPR-9 does not allow the forebrain seizure to manifest its typical behavioral concomitants despite electrographic evidence that spike–wave discharge is occurring in the forebrain.
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brainstem seizure severity regulates forebrain seizure expression in the audiogenic kindling model
Epilepsia, 2005Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: Although sound-induced (audiogenic) seizures in the Genetically Epilepsy-Prone Rat (GEPR) initially occur independent of the forebrain, repeated audiogenic seizures recruit forebrain seizure circuits in a process referred to as audiogenic kindling. In GEPR-3s, audiogenic kindling results in facial and forelimb (F&F) clonic seizures that are typical of forebrain seizures. However, in GEPR-9s, audiogenic kindling produces posttonic all-limb clonus not usually observed during forebrain seizures. We hypothesized that the more severe brainstem seizures of the GEPR-9 prevent the expression of F&F clonic seizures during audiogenic kindling. Therefore attenuation of audiogenic seizures during audiogenic kindling in GEPR-9s should allow F&F clonic seizures to be expressed. Likewise, intensifying audiogenic seizure severity in GEPR-3s should inhibit audiogenically kindled F&F clonic seizures. We have tested this hypothesis in the present study. Methods: Lesions of the superior colliculus or treatment with low-dose phenytoin were used to suppress audiogenic seizure severity in GEPR-9s. Depletion of brain serotonin was used to increase the seizure severity in GEPR-3s. All GEPRs were then subjected to audiogenic kindling. Behavioral and electrographic seizures were assessed. Results: Suppression of audiogenic seizure severity during audiogenic kindling in GEPR-9s increased the incidence forebrain seizure behavior. Kindled GEPR-9s that continued to display full tonic seizures did not exhibit forebrain convulsions, but did show posttonic clonus and forebrain seizure activity in the EEG. GEPR-3s chronically depleted of brain serotonin, along with displaying tonic brainstem seizures, tended to display less severe forebrain seizures during audiogenic kindling. Conclusions: These findings support the concept that severe brainstem seizures prevent the behavioral expression of forebrain seizures in audiogenically kindled GEPR-9s. It appears that the severe brainstem seizure of the GEPR-9 does not allow the forebrain seizure to manifest its typical behavioral concomitants despite electrographic evidence that spike–wave discharge is occurring in the forebrain.
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Role of the Superior Colliculus and the Intercollicular Nucleus in the Brainstem Seizure Circuitry of the Genetically Epilepsy-Prone Rat
Epilepsia, 2003Co-Authors: Michelle A Merrill, Phillip C Jobe, Richard W Clough, Ronald A. BrowningAbstract:Summary: Purpose: The neuronal network responsible for the convulsive behavior associated with sound-induced seizures in Genetically Epilepsy-Prone Rats (GEPRs) is believed to include the inferior colliculus and other brainstem structures such as the deep layers of the superior colliculus (DLSC), periaqueductal gray, and pontine reticular formation. However, previous studies also suggested that the DLSC and the nearby intercollicular nucleus (ICN) are part of a midbrain anticonvulsant zone capable of suppressing tonic convulsions when activated with bicuculline. Our aim in this study was to investigate the role of the superior colliculus (SC) and the ICN in generalized tonic–clonic seizures (GTCSs). Methods: Bilateral lesions of the SC and the ICN as well as bicuculline infusions into the ICN were used to assess the role of this dorsal midbrain region in brainstem seizures induced by sound stimulation in GEPR-9s and GEPR-3s. Results: Lesions of the SC markedly attenuated audiogenic seizure (AGS) severity by abolishing all behavioral components except the wild running. Lesions of the ICN significantly reduced seizure severity in GEPR-9s, but were somewhat less effective than SC lesions. Bicuculline infusion into the deep layers of the SC and/or the ICN produced audiogenic-like seizures in GEPR-9s. Conclusions: These findings support the hypothesis that the SC and ICN are important components of the brainstem seizure network, but suggest they are not necessary for the wild-running component of the seizure. The results further indicate that stimulation of the tectum facilitates GTCSs. Thus these findings suggest that the dorsal midbrain, when stimulated, is proconvulsant Rather than anticonvulsant regarding brainstem seizures in GEPRs.
Martin J Brodie - One of the best experts on this subject based on the ideXlab platform.
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regional expression of multidrug resistance genes in Genetically epilepsy prone Rat brain after a single audiogenic seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in Genetically Epilepsy-Prone Rat (GEPR) brain after a single audiogenic seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by seizure activity. Conclusions: These findings suggest that acute seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent seizure activity and to characterise mdr expression in other experimental seizure models.
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regional expression of multidrug resistance genes in Genetically epilepsy prone Rat brain after a single audiogenic seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in Genetically Epilepsy-Prone Rat (GEPR) brain after a single audiogenic seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by seizure activity. Conclusions: These findings suggest that acute seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent seizure activity and to characterise mdr expression in other experimental seizure models.