RESUMEN
To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7(-/-)). After the serendipitous discovery of a sensory stimulus-evoked epileptic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of these drugs induced seizures in mGluR7(-/-), but not in mGluR7(+/-), mice. PTZ-induced seizures were inhibited by three standard anticonvulsant drugs, but not by the group III selective mGluR agonist (R,S)-4-phosphonophenylglycine (PPG). Consistent with the lack of signs of epileptic activity in the absence of specific stimuli, mGluR7(-/-) mice showed no major changes in synaptic properties in two slice preparations. However, slightly increased excitability was evident in hippocampal slices. In addition, there was slower recovery from frequency facilitation in cortical slices, suggesting a role for mGluR7 as a frequency-dependent regulator in presynaptic terminals. Our findings suggest that mGluR7 receptors have a unique role in regulating neuronal excitability and that these receptors may be a novel target for the development of anticonvulsant drugs.
Asunto(s)
Predisposición Genética a la Enfermedad , Glicina/análogos & derivados , Receptores de Glutamato Metabotrópico/deficiencia , Convulsiones/genética , Animales , Anticonvulsivantes/farmacología , Bicuculina , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Convulsivantes , Resistencia a Medicamentos/genética , Electroencefalografía , Agonistas de Aminoácidos Excitadores/farmacología , Marcación de Gen , Glicina/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Homocigoto , Técnicas In Vitro , Ratones , Ratones Noqueados , Pentilenotetrazol , Fenotipo , Mapeo Físico de Cromosoma , Receptores de Glutamato Metabotrópico/genética , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Convulsiones/prevención & controlRESUMEN
(RS)-alpha-Methyl-4-phosphonophenylglycine (MPPG) and (S)-alpha-methyl-3-carboxyphenylalanine (M3CPA), two novel preferential antagonists of group III metabotropic glutamate (mGlu) receptors, antagonized the neuroprotective activity of L-2-amino-4-phosphono-butanoate (L-AP4) or L-serine-O-phosphate in mice cultured cortical cells exposed to a toxic pulse of N-methyl-D-aspartate. In contrast, MPPG did not influence the neuroprotective activity of the selective group II mGlu receptor agonist, (2S,1'R,2'R,3'R)-2-(2,3-dicarboxy-cyclopropyl) glycine (DCG-IV). These results indicate that activation of group III mGu receptors exerts neuroprotective activity against excitotoxic neuronal death. At least one of the two major group III mGlu receptor subtypes, i.e. mGlu4 receptor, is expressed by cultured cortical neurons, as shown by immunocytochemical analysis with specific polyclonal antibodies.