Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7.
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.
Sansig
G
G
Nervous System Department, Novartis Pharma AG, CH-4002 Basel, Switzerland.
Bushell
T J
TJ
Clarke
V R
VR
Rozov
A
A
Burnashev
N
N
Portet
C
C
Gasparini
F
F
Schmutz
M
M
Klebs
K
K
Shigemoto
R
R
Flor
P J
PJ
Kuhn
R
R
Knoepfel
T
T
Schroeder
M
M
Hampson
D R
DR
Collett
V J
VJ
Zhang
C
C
Duvoisin
R M
RM
Collingridge
G L
GL
van Der Putten
H
H
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001640:Bicuculline; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003292:Convulsants; D004351:Drug Resistance / Q000235:genetics; D004569:Electroencephalography; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006720:Homozygote; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D010433:Pentylenetetrazole; D010641:Phenotype; D020161:Physical Chromosome Mapping; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency* / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control
C119327:4-phosphonophenylglycine; D000927:Anticonvulsants; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D005998:Glycine; D010433:Pentylenetetrazole; D001640:Bicuculline