Increased Seizure Susceptibility in Mice Lacking Metabotropic Glutamate Receptor 7

Abstract

To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7 Ϫ/Ϫ ). 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 Ϫ/Ϫ , but not in mGluR7 ϩ/Ϫ , 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 Ϫ/Ϫ 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.

Molecular Targets for Antiepileptic Drug Development

“…Spontaneous mutations causing epilepsy are not known in mice or in humans; however, mice in which GluR7 has been deleted by gene targeting show an in-creased susceptibility to seizures and increased cortical excitability. 289 Acquired forms of epilepsy show marked changes in the expression and function of mGluRs. In the kindling model of epilepsy, there is upregulation of group I receptors that can be demonstrated by biochemical or electrophysiological functional assays.…”

mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity

“…37 We have validated a method for siRNA-induced knockdown in the mouse. 16 As many of the initial studies of mGluR7 have relied on information from mGluR7 knockout animals, 10,12,38,39 which are bred on a C57BL/6 background, we chose to conduct our siRNA studies on this background. Seventy-four male C57BL/6 mice (23-31 g; Charles River, France) were housed and surgeries performed as described previously, 15 40 ).…”

Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Dysregulation of the HPA Axis and Increases Hippocampal BDNF Protein Levels: Implications for Stress-Related Psychiatric Disorders

“…mGluR7 À/À mice were generated as described previously from E14 (129/Ola) embryonic stem cells (Sansig et al, 2001). Larger age-matched groups of mGluR7 À/À and mGluR7 + / + mice were generated using a specific pathogen-free (SPF) breeding colony of 30 F14, B6-mGluR7 + /À males mating with 60-90 F14, B6-mGluR7 + /À females.…”

“…Mice lacking mGluR7 have deficits in amygdala-dependent behaviors (fear response and conditioned taste aversion), but show no alterations in locomotor activity or pain sensitivity (Masugi et al, 1999). Electrophysiological analysis in mGluR7 À/À mice further suggests that this receptor is a frequency-dependent regulator of neurotransmitter release (Sansig et al, 2001), and modulates short-term synaptic plasticity in the hippocampus (Bushell et al, 2002). Moreover, we have demonstrated that mGluR7 ablation in mice is associated with changes in animal behavioral paradigms predictive of antidepressant and anxiolytic action, which suggests that drugs acting at mGluR7 may provide novel treatments for psychiatric disorders such as depression and anxiety (Cryan et al, 2003).…”