Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7

To study the role of mGlu7 receptors (mGluR7), we used homologous recombina tion to generate mice lacking this metabotropic receptor subtype (mGluR7(-/ -)). After the serendipitous discovery of a sensory stimulus-evoked epilept ic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of thes e 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-phosphonophenylglycin e (PPG). Consistent with the lack of signs of epileptic activity in the abs ence of specific stimuli, mGluR7(-/-) mice showed no major changes in synap tic properties in two slice preparations. However, slightly increased excit ability was evident in hippocampal slices. In addition, there was slower re covery from frequency facilitation in cortical slices, suggesting a role fo r mGluR7 as a frequency-dependent regulator in presynaptic terminals. Our f indings suggest that mGluR7 receptors have a unique role in regulating neur onal excitability and that these receptors may be a novel target for the de velopment of anticonvulsant drugs.