Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7

G. Sansig, T. Bushell, V.R. Clarke, A. Rozov, N. Burnashev, C. Portet, F. Gasparini, M. Schmutz, K. Klebs, R. Shigemoto, P.J. Flor, R. Kuhn, T. Knoepfel, M. Schroeder, D.R. Hampson, V.J. Collett, C. Zhang, R.M. Duvoisin, G.L. Collingridge, Herman van der Putten

Research output: Contribution to journalArticle

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Abstract

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.
LanguageEnglish
Pages8734-8745
Number of pages11
JournalJournal of Neuroscience
Volume21
Issue number22
Publication statusPublished - 2001

Fingerprint

Seizures
Pentylenetetrazole
Anticonvulsants
Convulsants
Bicuculline
Homologous Recombination
Presynaptic Terminals
metabotropic glutamate receptor 7
Pharmaceutical Preparations
Phenotype

Keywords

  • epilepsy
  • mGluR7
  • knock-out
  • mice
  • group III mGluR
  • (R
  • S)-4-phosphonophenylglycine
  • pharmacology

Cite this

Sansig, G., Bushell, T., Clarke, V. R., Rozov, A., Burnashev, N., Portet, C., ... van der Putten, H. (2001). Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. Journal of Neuroscience, 21(22), 8734-8745.
Sansig, G. ; Bushell, T. ; Clarke, V.R. ; Rozov, A. ; Burnashev, N. ; Portet, C. ; Gasparini, F. ; Schmutz, M. ; Klebs, K. ; Shigemoto, R. ; Flor, P.J. ; Kuhn, R. ; Knoepfel, T. ; Schroeder, M. ; Hampson, D.R. ; Collett, V.J. ; Zhang, C. ; Duvoisin, R.M. ; Collingridge, G.L. ; van der Putten, Herman. / Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. In: Journal of Neuroscience. 2001 ; Vol. 21, No. 22. pp. 8734-8745.
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abstract = "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.",
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author = "G. Sansig and T. Bushell and V.R. Clarke and A. Rozov and N. Burnashev and C. Portet and F. Gasparini and M. Schmutz and K. Klebs and R. Shigemoto and P.J. Flor and R. Kuhn and T. Knoepfel and M. Schroeder and D.R. Hampson and V.J. Collett and C. Zhang and R.M. Duvoisin and G.L. Collingridge and {van der Putten}, Herman",
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Sansig, G, Bushell, T, Clarke, VR, Rozov, A, Burnashev, N, Portet, C, Gasparini, F, Schmutz, M, Klebs, K, Shigemoto, R, Flor, PJ, Kuhn, R, Knoepfel, T, Schroeder, M, Hampson, DR, Collett, VJ, Zhang, C, Duvoisin, RM, Collingridge, GL & van der Putten, H 2001, 'Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7' Journal of Neuroscience, vol. 21, no. 22, pp. 8734-8745.

Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. / Sansig, G.; Bushell, T.; Clarke, V.R.; Rozov, A.; Burnashev, N.; Portet, C.; Gasparini, F.; Schmutz, M.; Klebs, K.; Shigemoto, R.; Flor, P.J.; Kuhn, R.; Knoepfel, T.; Schroeder, M.; Hampson, D.R.; Collett, V.J.; Zhang, C.; Duvoisin, R.M.; Collingridge, G.L.; van der Putten, Herman.

In: Journal of Neuroscience, Vol. 21, No. 22, 2001, p. 8734-8745.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7

AU - Sansig, G.

AU - Bushell, T.

AU - Clarke, V.R.

AU - Rozov, A.

AU - Burnashev, N.

AU - Portet, C.

AU - Gasparini, F.

AU - Schmutz, M.

AU - Klebs, K.

AU - Shigemoto, R.

AU - Flor, P.J.

AU - Kuhn, R.

AU - Knoepfel, T.

AU - Schroeder, M.

AU - Hampson, D.R.

AU - Collett, V.J.

AU - Zhang, C.

AU - Duvoisin, R.M.

AU - Collingridge, G.L.

AU - van der Putten, Herman

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - epilepsy

KW - mGluR7

KW - knock-out

KW - mice

KW - group III mGluR

KW - (R

KW - S)-4-phosphonophenylglycine

KW - pharmacology

UR - http://www.jneurosci.org/cgi/content/abstract/21/22/8734

M3 - Article

VL - 21

SP - 8734

EP - 8745

JO - Journal of Neuroscience

T2 - Journal of Neuroscience

JF - Journal of Neuroscience

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Sansig G, Bushell T, Clarke VR, Rozov A, Burnashev N, Portet C et al. Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. Journal of Neuroscience. 2001;21(22):8734-8745.