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The Journal of Neuroscience, November 15, 2001, 21(22):8734-8745
Increased Seizure Susceptibility in Mice Lacking Metabotropic
Glutamate Receptor 7
Gilles
Sansig1,
Trevor
J.
Bushell2,
Vernon R. J.
Clarke2,
Andrei
Rozov3,
Nail
Burnashev3,
Chantal
Portet1,
Fabrizio
Gasparini1,
Markus
Schmutz1,
Klaus
Klebs1,
Ryuichi
Shigemoto4,
Peter J.
Flor1,
Rainer
Kuhn1,
Thomas
Knoepfel1,
Markus
Schroeder1,
David R.
Hampson5,
Valerie J.
Collett2,
Congxiao
Zhang6,
Robert M.
Duvoisin6,
Graham L.
Collingridge2, and
Herman
van der
Putten1
1 Nervous System Department, Novartis Pharma AG,
CH-4002 Basel, Switzerland, 2 Medical Research Council
Center for Synaptic Plasticity, Department of Anatomy, The School of
Medical Sciences, University of Bristol, Bristol, BS8 1TD, United
Kingdom, 3 Abteilung Zellphysiologie, Max-Planck-Institut
für Medizinische Forschung, D-69120 Heidelberg, Germany,
4 Division of Cerebral Structure, National Institute for
Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan,
5 Faculty of Pharmacy and Department of Pharmacology,
University of Toronto, Ontario, Canada M5S 2S2, and
6 Margaret M. Dyson Vision Research Institute, Department
of Ophthalmology, Cornell University Medical College, New York, New
York 10021
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.
Key words:
epilepsy; mGluR7; knock-out; mice; group III mGluR; (R,S)-4-phosphonophenylglycine
Copyright © 2001 Society for Neuroscience 0270-6474/01/21228734-12$05.00/0
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