Alterations of Gaba - Mediated Synaptic Transmission in Human Epilepsy

Lloyd, Kenneth G.; Bossi, Laura; Morselli, P. L.; Munari, C.; Rougier, Marie-Bénédicte; Loiseau, P

doi:10.1097/00002826-198406001-00192

Cited by 45 publications

(53 citation statements)

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“…Thus, such a screening model will likely be capable of identifying compounds with different mechanisms of action. According to the data from patients with epilepsy, GAD activity is decreased in the cortex [36], and upregulation of GAD isoforms (GAD65 and GAD67) has been described in the remaining GABAergic neurons in a model of temporal lobe epilepsy [73]. Moreover, GAD autoantibodies have been detected in patients with treatment-refractory epilepsy [74].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it has been suggested that convulsions may arise from either an impairment of GABAergic and/or excessive glutamatergic function [33][34][35]. Accordingly, although no consistent correlation was reported between ictal foci and reduced GABA levels in patients with drugrefractory seizures, glutamate decarboxylase (GAD, EC 4.1.1.15) activity was significantly decreased in the human cortex [36]. Interestingly, (D,L)-allylglycine (AG, 2-amino-4-pentenoic acid) interferes with the synthesis of GABA via a mixed-mechanism inhibition of GAD, leading to decreased GABA levels [37] and increased glutamine concentrations in the brain [38,39], with glutamate levels remaining unchanged in these studies.…”

Section: Introductionmentioning

confidence: 99%

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Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be timeconsuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (D,L)-Allylglycine inhibits glutamic acid decarboxylase (GAD) -the key enzyme in γ-aminobutyric acid (GABA) biosynthesis -leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD 50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated crossspecies similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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“…In the hippocampus, intrinsic GABAergic neurones are driven by afferent fibres and local pyramidal cells to bring about feedforward and feedback inhibition, respectively (Andersen, Eccles & Loyning, 1963;Alger & Nicoll, 1982). Although the exact function of GABAergic inhibition in the integrative activity of the cortex remains unclear, its importance is underscored by studies showing that the pharmacological blockade of GABAA receptor lead to epileptiform activity (Schwartzkroin & Prince, 1980) and that deficiencies in the GABAergic inhibitory system may be involved in some forms of human epilepsy (Lloyds, Bossi, Morselli, Munari, Rougier & Loiseau, 1986). In addition, modification of inhibition may be involved in both short-term (Ben-Ari, Krnjevic & Reinhardt, 1979;XXTong & Wlatkins, 1982;McCarren &, Alger, 1985;Thompson & Gaehwiler, 1989) and long-term (Stelzer, Slater & ten Bruggencate, 1987; Miles & Wong, 1987) changes in neuronal activity following tetanic stimulation of afferent fibres to the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea‐pig hippocampal neurones.

Chen

Stelzer

Kay

et al. 1990

The Journal of Physiology

291

166

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SUMMARY1. Current mediated by GABAA receptors was examined in pyramidal cells acutely dissociated from the hippocampus of mature guinea-pigs. Current responses were measured using whole-cell voltage-clamp recordings. An internal perfusion technique was used to change the intracellular contents during recording.2. Application of GABA (100-300 /M) by short duration pressure pulses produced outward current responses at a holding potential of -10 mV. When recordings were made with intracellular solutions which did not contain Mg-ATP, GABA responses progressively decreased to less than 10% of their initial values after 10 min. This 'run-down' of the GABA response could not be accounted for by desensitization since the rate of run-down was not dependent upon agonist application.3. The run-down of the GABAA response was reversed when Mg2+ (4 mM) and ATP (2 mM) were introduced into the intracellular perfusate. In addition to the presence of Mg-

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“…Instead, the lower GABA levels in the CSF of these patients after GVG treatment could be related to the degree of destruction of their GABAergic neurons. In surgical samples from patients with partial epilepsy a defect in GABA neurons and/or neurotransmission is found in about 50-70% of these patients (Lloyd et al, 1986). The number of GABA-synthesizing neurons in nonresponders might be destroyed even more than in responders, thus resulting in lower GABA levels even in the presence of GVG-induced metabolic inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Neuroanatomical, neurochemical, and neuropharmacological studies have recently demonstrated that the balance between inhibitory and excitatory neurotransmission is important for the initiation of focal seizures (Gale, 1986;Turski et al, 1986). Studies of brain samples taken during epilepsy surgery suggest that in about 50-70% of the patients with CPS GABAergic transmission is impaired (Lloyd et al, 1986). GABA seems to be the major inhibitory neurotransmitter in the different nigral efferents, which modulate the spread of the motor component of seizures in rats (Gale, 1986;McNamara et al, 1983).…”

Section: Introductionmentioning

confidence: 99%