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The Journal of Neuroscience, August 15, 2000, 20(16):6218-6224

Modulation of Absence Seizures by the GABA_A Receptor: A Critical Role for Metabotropic Glutamate Receptor 4 (mGluR4)

O. Carter Snead III^{1, 4, 5, 6}, P. K. Banerjee^{1, 5, 6}, McIntyre Burnham^{2, 4}, and David Hampson^{2, 3}

Departments of ¹ Pediatrics and ² Pharmacology, ³ Faculty of Pharmacy, and ⁴ Bloorview Epilepsy Program, University of Toronto, Toronto, Ontario, Canada, and ⁵ Division of Neurology and the ⁶ Program in Brain and Behavior, Hospital for Sick Children, Toronto, Ontario, Canada

Experimental absence seizures are associated with perturbations in the presynaptic release of GABA and glutamate within thalamocortical circuitry. The release of both glutamate and GABA is regulated by group III metabotropic glutamate receptors (mGluRs). Therefore, we examined the susceptibility of mice lacking the mGluR4 subtype of mGluR (mGluR4^/) versus their wild-type controls (mGluR4^+/+) to absence seizures induced either by -hydroxybutyrate (GHB) or the GABA_B agonist () baclofen or by low doses of the GABA_A receptor (GABA_AR) antagonists pentylenetetrazole, bicuculline, or picrotoxin. There was no difference between mGluR4^/ and mGluR4^+/+ mice in threshold to absence seizures induced by either GHB or () baclofen. In contrast, the mGluR4^/ mice were markedly resistant to absence seizures induced by low doses of GABA_AR antagonists. No differences were observed between mGluR4^/ and mGluR4^+/+ mice in threshold to clonic or tonic seizures induced by higher doses of GABA_AR antagonists, strychnine, or electroshock, indicating that seizure resistance in the mGluR4^/ mice was restricted solely to absence seizures. The resistance of mGluR4^/ mice to absence seizures induced by GABA_AR antagonists was mimicked by bilateral administration of a mGluR4 antagonist into the nucleus reticularis thalami (nRT) of mGluR4^+/+ mice. Conversely, intra-nRT administration of a mGluR4 agonist in mGluR4^+/+ mice exacerbated GABA_AR-induced absence seizures. These data indicate that the presence of mGluR4 within nRT is critical to GABAergic modulation of thalamocortical synchronization in normal and pathological states, such as generalized absence epilepsy.

Key words: group III metabotropic glutamate receptors; thalamus; thalamocortical; mGluR4; absence seizures; GABA

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20166218-07$05.00/0

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