Modulation of absence seizures by the GABAA receptor: A critical role for metabotropic glutamate receptor 4 (mGluR4)

Experimental absence seizures are associated with perturbations in the pres ynaptic 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-ty pe controls(mGluR4(+/+)) to absence seizures induced either by gamma-hydrox ybutyrate (GHB) or the GABA(B) agonist (-) baclofen or by low doses of the GABA(A) receptor (GABA(A)R) antagonists pentylenetetrazole, bicuculline, or picrotoxin. There was no difference between mGluR4(-/-) and mGluR4(+/+) mi ce in threshold to absence seizures induced by either GHB or (2) baclofen. In contrast, the mGluR4(-/-) mice were markedly resistant to absence seizur es induced by low doses of GABAAR antagonists. No differences were observed between mGluR4(-/-) and mGluR4(+/+) mice in threshold to clonic or tonic s eizures induced by higher doses of GABA(A)R antagonists, strychnine, or ele ctroshock, indicating that seizure resistance in the mGluR4(+/+) mice was r estricted solely to absence seizures. The resistance of mGluR4(+/+) mice to absence seizures induced by GABA(A)R 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 mGluR 4 agonist in mGluR4(+/+) mice exacerbated GABA(A)R-induced absence seizures . These data indicate that the presence of mGluR4 within nRT is critical to GABAergic modulation of thalamocortical synchronization in normal and path ological states, such as generalized absence epilepsy.