Pathophysiological mechanisms of genetic absence epilepsy in the rat

Danober, Laurence; Deransart, Colin; Depaulis, Antoine; Vergnes, Marguerite; Marescaux, Christian

doi:10.1016/s0301-0082(97)00091-9

Cited by 513 publications

(498 citation statements)

References 309 publications

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“…In that study, a GABA-withdrawal syndrome induced after suppression of a 2-h intracortical GABA infusion was used as a model of focal epileptogenesis (18). Taken together, it has been suggested that GAERS are hyperresponsive to GABA A antagonists (19). The outcomes of our study are in agreement with this hypothesis and previous findings from our laboratory.…”

Section: Figsupporting

confidence: 90%

Cardiovascular Regulation through Hypothalamic GABA_A Receptors in a Genetic Absence Epilepsy Model in Rat

Aker

Onat

2002

Epilepsia

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Summary:Purpose: ␥-Aminobutyric acid (GABA) plays a vital role in both central cardiovascular homeostasis and pathogenesis of epilepsy. Epilepsy affects autonomic nervous system functions. In this study, we aimed to clarify the role of GABA A receptors in hypothalamic cardiovascular regulation in a genetically determined animal model of absence epilepsy.Methods: Nonepileptic Wistar rats and genetic absence epilepsy rats from Strasbourg (GAERS) were instrumented with a guide cannula for drug injection and extradural electrodes for EEG recording. After a recovery period, iliac arterial catheters were inserted for direct measurement of mean arterial pressure and heart rate. Bicuculline, a GABA A -receptor antagonist, was injected into the dorsomedial (DMH) or posterior (PH) hypothalamic nuclei of nonepileptic control rats or GAERS. Blood pressure, heart rate, and EEG recordings were performed in conscious unrestrained animals.Results: Bicuculline injections into the hypothalamus produced increases in blood pressure and heart rate of both control rats and GAERS. The DMH group of GAERS showed a twofold increase in the blood pressure and the heart rate compared with those of control rats. Pressor responses to bicuculline, when microinjected into the PH, were similar in the nonepileptic animals and GAERS. Conversely, the amplitude of tachycardic responses to the administration of bicuculline into the PH was significantly higher in GAERS compared with those of control rats. Conclusions:The bicuculline-induced increases in blood pressure and heart rate were more prominent when given in the DMH of GAERS. These results indicate an increased GABA A receptor-mediated cardiovascular response through the DMH in conscious rats with absence epilepsy.

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Section: Figsupporting

confidence: 90%

Cardiovascular Regulation through Hypothalamic GABA_A Receptors in a Genetic Absence Epilepsy Model in Rat

Aker

Onat

2002

Epilepsia

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“…Thus, the functional and anatomic integrity of thalamus and cortex is required for generalized spike-and-wave discharges in the feline penicillin model. Similar conclusions have been drawn from studies with various rat strains that exhibit absence-like seizures (54,63,64).…”

Section: Pathophysiology Of Absence Attackssupporting

confidence: 78%

“…nisms in spike-and-wave generation is supported by pharmacologic studies showing that microinjection GABA A -or GABA B -receptor agonists into the thalamic relay nuclei increase the duration of the spike-and-wave discharges in the GAERS rat (54). In contrast, spike-andwave discharges are abolished by microinjection of GABA B -receptor antagonists.…”

Section: Fig 3 a Bmentioning

confidence: 87%

“…The validity of the corticoreticular hypothesis has been tested over the years in several models of absence attacks with generalized spike-and-wave discharges (50)(51)(52)(53)(54)(55)(56). These studies have demonstrated a similarity between the synchronized activity occurring in thalamocortical circuits during sleep spindles and the spike-andwave discharges of absence epilepsy in the awake state.…”

Section: Pathophysiology Of Absence Attacksmentioning

confidence: 99%

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Generalized Epileptic Disorders: An Update

2001

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“…Abnormal hypersynchronized oscillatory activities in the thalamocortical network, consisting of feedforward and feedback connections between the cortex and the thalamus, have been implicated as an underlying mechanism for the generation of SWDs (5)(6)(7)(8)(9). Some studies using rat models of absence seizures have suggested that the cortex plays a leading role in the generation of SWDs (10)(11)(12)(13).…”

mentioning

confidence: 99%

Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures

Cheong

Zheng

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Absence seizures are characterized by cortical spike-wave discharges (SWDs) on electroencephalography, often accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing driven by T-type Ca 2؉ currents. We recently demonstrated that the phospholipase C ␤4 (PLC␤4) pathway tunes the firing mode of TC neurons via the simultaneous regulation of T-and L-type Ca 2؉ currents, which prompted us to investigate the contribution of TC firing modes to absence seizures. PLC␤4-deficient TC neurons were readily shifted to the oscillatory burst firing mode after a slight hyperpolarization of membrane potential. TC-limited knockdown as well as whole-animal knockout of PLC␤4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLC␤4 leads to the genesis of absence seizures. The SWDs were effectively suppressed by thalamic infusion of a T-type, but not an L-type, Ca 2؉ channel blocker. These results reveal a primary role of TC neurons in the genesis of absence seizures and provide strong evidence that an alteration of the firing property of TC neurons is sufficient to generate absence seizures. Our study presents PLC␤4-deficient mice as a potential animal model for absence seizures.epilepsy ͉ gene knockdown ͉ knockout mice ͉ thalamus A bsence seizures are generalized nonconvulsive seizures characterized by a brief and sudden impairment of consciousness, concomitant with bilaterally synchronized spike-and-wave discharges (SWDs) in the electroencephalogram (EEG) over wide cortical areas (1-4). Abnormal hypersynchronized oscillatory activities in the thalamocortical network, consisting of feedforward and feedback connections between the cortex and the thalamus, have been implicated as an underlying mechanism for the generation of SWDs (5-9). Some studies using rat models of absence seizures have suggested that the cortex plays a leading role in the generation of SWDs (10-13). Other studies support the hypothesis that massive thalamocortical synchronization is driven from recurrent oscillatory activities in the network between reticular thalamic nucleus (nRT) and thalamocortical (TC) relay nucleus (3,8,9,14,15). A majority of these studies proposed a leading role for nRT neurons in the genesis of absence seizures. Relatively less attention has been directed on the role of TC neurons in the generation of SWDs. Thalamocortical network oscillations are often observed to be accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing (16). Low-threshold burst firing driven by T-type Ca 2ϩ currents in TC neurons has long been proposed to be a critical component in sustaining the oscillations during the SWDs (3,8,17), although a controversy still remains (4, 18).Many studies have described spontaneous appearance of SWDs in the cortical EEG from rodent models for absence epilepsy (19)(20)(21)(22)(23)(24). Some showed that T-type Ca 2ϩ currents were incre...

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Pathophysiological mechanisms of genetic absence epilepsy in the rat

Cited by 513 publications

References 309 publications

Cardiovascular Regulation through Hypothalamic GABA_A Receptors in a Genetic Absence Epilepsy Model in Rat

Cardiovascular Regulation through Hypothalamic GABA_A Receptors in a Genetic Absence Epilepsy Model in Rat

Generalized Epileptic Disorders: An Update

Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures

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Pathophysiological mechanisms of genetic absence epilepsy in the rat

Cited by 513 publications

References 309 publications

Cardiovascular Regulation through Hypothalamic GABAA Receptors in a Genetic Absence Epilepsy Model in Rat

Cardiovascular Regulation through Hypothalamic GABAA Receptors in a Genetic Absence Epilepsy Model in Rat

Generalized Epileptic Disorders: An Update

Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures

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Cardiovascular Regulation through Hypothalamic GABA_A Receptors in a Genetic Absence Epilepsy Model in Rat

Cardiovascular Regulation through Hypothalamic GABA_A Receptors in a Genetic Absence Epilepsy Model in Rat