Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation

Metabotropic receptors coupled to G(q)/G(11) family G proteins critically contribute to nervous system functions by modulating synaptic transmission, often facilitating excitation. We investigated the role of G(q)/G(11) family G proteins in the regulation of neuronal excitability in mice that selectively lack the alpha-subunits of G(q) and G(11), G alpha(q) and G alpha(11), 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)/G(11) family G proteins negatively regulate neuronal excitability in vivo and suggest that impaired endocannabinoid formation in the absence of G(q)/G(11) contributes to this phenotype.