Abstract
Generalized absence seizures in humans are a unique type of epilepsy characterized by a synchronous, bilateral 3-Hz spike and wave discharge emanating from a cortical and thalamic network within the brain. The availability of a number of pharmacological and genetic animal models has provided us with the means with which to investigate the cellular and molecular mechanisms underlying these seizures. Over the last few years a significant amount of research in these models has focused on the role of the inhibitory GABAB receptors, which have been previously described in a number of brain areas as being responsible for a long-lasting hyperpolarization and depression in neurotransmitter release. Initial studies provided evidence that the GABAB receptor was capable of generating the low threshold calcium spike required for initiation of the burst firing, leading researchers to hypothesize that the GABAB receptors, played a significant role in these seizures. Subsequent research took advantage of the new generation of GABAB antagonists that became available in the early 1990s and demonstrated that in a number of models the seizures could be abolished by the administration of one of these compounds. Further biochemical, molecular, and electrophysiological experiments have been carried out to determine the exact involvement of GABAB receptors and their mechanism of action. The current evidence and interpretations of this work are presented here.
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Avanzini G., Vergnes M., Spreafico R., and Marescaux C. (1993) Calcium dependent regulation of genetically determined spike and waves by the reticular thalamic nucleus of rats.Epilepsia 34, 1–7.
Avoli M. (1987) Mechanisms of generalized epilepsy with spike and wave discharge.EEG Suppl. 39, 184–190.
Avoli M. and Gloor P. (1982) Role of the thalamus in generalized penicillin epilepsy: observations on decorticated cats.Exp. Neurol. 77, 386–402.
Avoli M., Gloor P., Kostopoulos G., and Gotman J. (1983) An analysis of penicillin-induced generalized spike and wave discharges using simultaneous recordings of cortical and thalamic single neurons.J. Neurophysiol. 50, 819–837.
Banerjee P. K. and Snead O. C. III (1995) Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acid B (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GHB.J. Pharmacol. Exp. Ther. 273(3), 1534–1543.
Berkovic S. F. (1993) Generalized absence seizures, inThe Treatment of Epilepsy: Principles and Practice (Wyllie E., ed.), Lea & Febiger. Philadelphia, PA, pp. 401–411.
Bittiger H., Bernasconi R., Froestl W., Hall J., Jaekel K., Klebs L., Mickel S. J., Mondadori C., Olpe H.-R., Pfannkuck F., Pozza M., Probst A., Van Reizen H., Schmutz M., Schuetz H., Steinmann M. W., Vassout A., and Waldermeir P. (1992) GABAB antagonists: potential new drugs.Pharmacol. Comm. 2, 70–74.
Bolser D. C., Blythin D. J., Chapman R. W., Egan R. W., Hey J. A., Rizzo C., Kuo S.-C., and Kreutner W. (1995) The pharmacology of SCH 50911: a novel, orally active GABAB receptor antagonist.J. Pharmacol. Exp. Ther. 274, 1393–1398.
Bowery N. G., Hill D. R., Hudson A. L., Dolble A., Middlemass D. N., Shaw J., and Timbull M. J. (1980) (−) Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor.Nature 283, 92–94.
Caddick S. J. and Hosford D. A. (1996) GABAB activated gK+ in thalamic neurons in the lethargic (lh/lh) mouse model of generalized absence seizures.N. Lett. 205, 29–32.
Coulter D. A., Huguenard J. R., and Prince D. A. (1989a) Characterization of ethosuximide reduction of low threshold calcium current in thalamic neurons.Ann. Neurol. 25, 582–593.
Coulter D. A., Huguenard J. R., and Prince D. A. (1989b) Calcium currents in rat thalamocortical relay neurons: kinetic properties of the transient, low-threshold current.J. Physiol. 414, 587–604.
Coulter D. A., Huguenard J. R., and Prince D. A. (1989c) Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons.N. Lett. 98, 74–78.
Coulter D. A., Huguenard J. R., and Prince D. A. (1990) Differential effects of petit mat anticonvulsants and convulsants on thalamic neurons: calcium current reduction.B. J. Pharm. 100, 800–806.
Crunelli V., Lightowler S., and Pollard S. E. (1989) A T-type Ca2+ current underlies low threshold Ca2+ potentials in cells of the rat and cat lateral geniculate nucleus.J. Physiol. 413, 543–561.
Crunelli V. and Leresche N. (1991) A role for GABAB receptors in excitation and inhibition of thalamocortical cells.Trends Neurosci. 14, 16–21.
Froestl W., Mickel S. J., Von Sprecher G., Bittiger H., and Olpe H. R. (1992) Chemistry of new GABAB antagonists.Pharmacol. Comm. 2, 52–56.
Godschalk M., Dzoljic M. R., and Bonta I. L. (1976) Antagonism of gamma-hydroxybutyrate-induced hypersynchronization in the EcoG of the rat by anti petit mat drugs.Neurosci. Lett. 3, 145–150.
Gloor P. (1979) Generalized epilepsy with spike-and-wave discharge: a reinterpretation of its electrographic and conical manifestations.Epilepsia 20, 571–584.
Gloor P. and Fariello R. G. (1988) Generalized epilepsy: some of its cellular mechanisms differ from those of focal epilepsy.Trends Neurosci. 11, 63–68.
Golden G. T. and Fariello R. G. (1984) Epileptogenic action of some GABA agonists: effects of manipulation of the GABA and glutamate systems, inNeurotransmitters, Seizures and Epilepsy II (Fariello R. G. et al., eds.), Raven, New York, pp. 237–244.
Hill D. R. and Bowery N. G. (1981)3H-baclofen and3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain.Nature 290, 149–52.
Hosford D. A., Wang Y., Liu C. C., and Snead O. C. (1995a) Characterization of the anti-absence effects of SCH 50911, a GABAB receptor antagonist, in the lethargic mouse, gamma-hydroxybutyrate and pentylenetetrazole models.J. Pharmacol. Exp. Ther. 274, 1399–1403.
Hosford D. A., Lin F.-H., Kraemer D. L., Cao Z., Wang Y., and Wilson J. T. (1995b) Neural network of structures in which GABAB receptors regulate absence seizures in the lethargic (lh/lh) mouse model.J. Neurosci. 15, 7367–7376.
Hosford D. A., Lin F.-H., Cao Z., Wang Y., Kraemer D. L., and Wilson J. T. (1994) Action of anti-epileptic drugs in animal models: mechanistic framework of absence seizures with a focus on the lethargic (lh/lh) mouse model, inTypical Absences and Related Epileptic Syndromes (Duncan J. S. and Panayiotopoulos C. P., eds.), Churchill-Livingstone, London, pp. 41–50.
Hosford D. A., Clark S., Cao Z., Wilson W. A., Lin F.-H., Morrisett R. A., and Huin A. (1992) The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice.Science 257, 398–401.
Houser C. R., Vaughn J. E., Barker R. P., and Roberts E. (1980) GABA neurons are the major cell type of the nucleus reticularis thalami.Brain Res. 200, 431–435.
Huguenard J. R. and Prince D. A. (1994) Clonazepam suppresses GABAB-mediated inhibition in thalamic relay neurons through effects in nucleus reticularis.J. Neurophys. 71, 2576–2581.
Huguenard J. R. and Prince D. A. (1992) A novel T-type current underlies prolonged Ca2+-dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus.J. Neurosci. 12, 3804–3817.
Huguenard J. R., Coulter D. A., and Prince D. A. (1991) A fast transient potassium current in thalamic relay neurons: kinetics of activation and inactivation.J. Neurophysiol. 66, 1304–1315.
Jasper H. H. and Droogleever-Fortuyn J. (1946) Experimental studies on the functional anatomy of petit mal epilepsy.Res. Publ. Assoc. Nerv. Ment. Dis. 26, 272–298.
Knight A. R. and Bowery N. G. (1992) GABA receptors in rats with spontaneous generalized non-convulsive epilepsy.J. Neural. Transm. 35(Suppl.), 189–196.
Lin F.-H., Cao Z., and Hosford D. A. (1993) Selective increases in GABAB receptor number in lethargic (lh/lh) mouse model of absence seizures.Brain Res. 608, 101–106.
Lin F.-H., Wang Y., Lin S., Cao Z., and Hosford D. A. (1995) GABAB receptor mediated effects in synaptosomes of lethargic (lh/lh) mice.J. Neurochem. 65, 2087–2095.
Marescaux C., Vergnes M., and Depaulis A. (1992a) Genetic absence epilepsy in rats from Strasbourg— a review.J. Neural Transm. 35(Suppl.), 37–69.
Marescaux C., Vergnes M., and Bernasconi R. (1992b) GABAB receptor antagonists: potential new antiabsence drugs.J. Neural Transm. 35(Suppl.), 179–188.
Meldrum B. S. and Horton R. W. (1974) Neuronal inhibition mediated by GABA and patterns of convulsions in baboons with photosensitive epilepsy (Papio papio), inEpilepsy (Harris, P. and Mawdsley C., eds.), Churchill Livingstone, Edinburgh, pp. 55–65.
Mott D. D. and Lewis D. V. (1994) The pharmacology and function of central GABAB receptors.Int. Rev. Neurobiol. 36, 97–223.
Noebels J. L. (1986) Mutational analysis of inherited epilepsies, inBasic Mechanisms of the Epilepsies (Delgado-Escueta A. V., Ward A. A., Woodbury D. M., and Poster R. J., eds.), Raven, New York, pp. 97–113.
Olpe H.-R., Karlsson, G., Pozza M. F., Brugger F., Steinmann M., Van Reizen H., Fagg G., Hall, R. G., Froestl W., and Bittiger H. (1990) CGP 35348: a centrally active blocker of GABAB receptors.Eur. J. Pharmacol. 187, 27–38.
Pellegrini A. and Gloor P. (1979) Effects of bilateral partial diencephalic lesions on cortical and epileptic activity in generalized penicillin epilepsy in the cat.Neurology 19, 309–310.
Porter R. J. (1993) The absence epilepsies.Epilepsia 34(Suppl. 3), 542–548.
Prince D. and Farrell D. (1969) “Centrencephalic” spike wave discharges following parenteral penicillin injection in the cat.Exp. Neurol. 66, 285–308.
Sato S., White B. G., Penry J. K., Dreifuss F. E., Sackellares J. C., and Kupferberg H. J. (1982) Valproic acid versus ethosuximide in the treatment of absence seizures.Neurology 32, 157–163.
Sidman R. L., Green M. C., and Appel S. H. (1965)Catalog of the Neurological Mutants of the Mouse. Harvard University Press, Cambridge, MA, 1965.
Snead O. C. (1995) Basic mechanisms of generalized absence seizures.Ann. Neurol. 37, 146–157.
Snead O. C. (1994) The ontogeny of [3H]γ-hydroxybutyrate and [3H]GABAB binding sites: relation to the development of experimental absence seizures.Brain Res. 659, 147–156.
Snead O. C., Banerjee P. K., and Liu C. C. (1993) The GABAB receptor in experimental models of generalized absence seizures in rats.Soc. Neurosci. Abst. 21, 1477.
Snead O. C. (1992a) Evidence for GABAB mediated mechanisms in experimental generalized absence seizures.Eur. J. Pharmacol. 213, 343–349.
Snead O. C. (1992b) Pharmacological models of generalized absence seizures in rodents.J. Neural Transm. 35(Suppl.), 7–19.
Snead O. C. (1992c) Evidence for G-protein modulation of experimental generalized absence seizures in rats.N. Lett. 142, 15–18.
Snead O. C. (1978) Gamma hydroxybutyrate in the monkey: III. Effect of intravenous anticonvulsant drugs.Neurology 28, 1173–1178.
Snead O. C., Hechler V., Vergnes M., Marescaux C., and, Maitre M. (1990) Increased GHB receptors in thalamus of a generic animal model of petitmal epilepsy.Epilepsy Res. 7(2), 121–128.
Snead O. C., Yu R. K., and Huttenlocher P. R. (1976) Gamma-hydroxybutyrate: a correlation of serum and cerebrospinal fluid levels with electroencephalographic and behavioural effects.Neurology 26, 51–56.
Steriade M. and Llinas R. F. (1988) The functional states of the thalamus and the associated neuronal interplay.Physiol. Rev. 68, 649–742.
Steriade M., McCormick D. A., and Sejnowski T. (1993) Thalamocortical oscillations in the sleeping and aroused brain.Science 262, 679–685.
Vergnes M., Marescaux C., Micheletti G., Reis J., Depaulis A., Rumbach L., and Warter J. M. (1982) Spontaneous paroxysmal electroclinical patterns in rat: a model of generalized non-convulsive epilepsy.Neurosci. Lett. 33, 97–101.
Vergnes M., Marescaux C., Micheletti G., Depaulis A., Rumbach L., and Warter J. M. (1984) Enhancement of spike and wave discharges by GABA mimetic drugs in rats with spontaneous petit mal like epilepsy.Neurosci. Lett. 44, 91–94.
von Krosigk M., Bal T., and McCormick D. A. (1993) Cellular mechanisms of a synchronized oscillation in the thalamus.Science 261, 361–364.
White G., Lovinger D. M., and Weight F. F. (1989) Transient low-threshold Ca2+ current triggers burst fling through an afterdepolarizing potential in an adult mammalian neuron.Proc. Natl. Acad. Sci. USA 86, 6802–6806.
Williams D. S. (1953) A study of thalamic and cortical rhythms in petit mat.Brain 76, 50–69.
Williams S. R., Turner J. P., and Crunelli V. (1995) Gamma-hydroxybutyrate promotes oscillatory activity of rat and cat thalamocortical neurons by a tonic GABAB receptor-mediated hyperpolarization.Neuroscience 66, 133–141.
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Caddick, S.J., Hosford, D.A. The role of GABAB mechanisms in animal models of absence seizures. Mol Neurobiol 13, 23–32 (1996). https://doi.org/10.1007/BF02740750
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DOI: https://doi.org/10.1007/BF02740750