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Forebrain-Specific Inactivation of G_q/G₁₁ Family G Proteins Results in Age-Dependent Epilepsy and Impaired Endocannabinoid Formation

Nina Wettschureck,¹ Mario van der Stelt,^2, Hiroshi Tsubokawa,³ Heinz Krestel,^4, Alexandra Moers,¹ Stefania Petrosino,² Günther Schütz,⁵ Vincenzo Di Marzo,^2* and Stefan Offermanns^1*

Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany,¹ Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli (NA), Italy,² Laboratory of Life Fluctuomatics, Graduate School of Information Sciences, Tohoku University, 09 Aoba, Aobaku-Aramaki, Sendai 980-8579, Japan,³ Max Planck Institute for Medical Research, Jahnstr. 29, 69120 Heidelberg, Germany,⁴ Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany⁵

Received 7 March 2006/ Returned for modification 28 April 2006/ Accepted 11 May 2006

Metabotropic receptors coupled to G_q/G₁₁ family G proteins critically contribute to nervous system functions by modulating synaptic transmission, often facilitating excitation. We investigated the role of G_q/G₁₁ family G proteins in the regulation of neuronal excitability in mice that selectively lack the -subunits of G_q and G₁₁, G_q and G₁₁, respectively, in forebrain principal neurons. Surprisingly, mutant mice exhibited increased seizure susceptibility, and the activation of neuroprotective mechanisms was impaired. We found that endocannabinoid levels were reduced under both basal and excitotoxic conditions and that increased susceptibility to kainic acid could be normalized by the enhancement of endocannabinoid levels with an endocannabinoid reuptake inhibitor, while the competitive cannabinoid type 1 receptor antagonist SR141716A did not cause further aggravation. These findings indicate that G_q/G₁₁ family G proteins negatively regulate neuronal excitability in vivo and suggest that impaired endocannabinoid formation in the absence of G_q/G₁₁ contributes to this phenotype.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: N.V. Organon, Molenstraat 110, 5340 BH Oss, The Netherlands.

Present address: Pharmacology and Toxicology, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.

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