Endocannabinoid system calms down seizures

Abstract

Research in mice suggests that the endocannabinoid system could be a therapeutic target for the treatment of epilepsy. Krisztina Monory, Giovanni Marsicano, Beat Lutz (Max-Planck Institute of Psychiatry, Munich, Germany, and Johannes Gutenberg University, Mainz, Germany), and colleagues report that this system provides protection against acute epileptiform seizures in mice by directly targeting hippocampal glutamatergic neurons. “Our results suggest that it might be possible to use drugs that enhance local concentrations of endocannabinoids to control epilepsy”, says Marsicano (now at AVENIR INSERM, Institute Francois Magendie, Bordeaux, France). However, the researchers warn that this step is only the fi rst towards understanding how the endocannabinoid system protects the brain against epilepsy. The endocannabinoid system helps to control neuronal excitability. “Endocannabinoids are produced and released from neuronal membranes when neurons are stimulated”, explains Marsicano, “and because their inactivation is rapid, they provide on-demand protection against excito toxicity”. Epileptic seizures are associated with an imbalance between excitatory glutamatergic transmission and inhibitory GABAergic transmission, continues Lutz, “so understanding how the endocannabinoid system controls excitatory transmission could provide new insights into epilepsy”. The researchers knocked out the gene for the endocannabinoid type1 receptor (CB1) on diff erent subsets of neurons in mice before injecting kainic acid (KA), which induces seizures. Mice expressing no CB1 in forebrain GABAergic neurons were no more susceptible to acute KAinduced seizures than were wild-type mice, but mice in which CB1 had been deleted in cortical glutamatergic neurons were very susceptible to seizures. Virally induced CB1 deletion in glutamatergic neurons in the hippocampus also increased the severity of KA-induced seizures (Neuron 2006; 51: 455–66). “We were very surprised by our results”, says Marsicano, “because CB1 is expressed highly on GABAergic neurons but only weakly on glutamatergic neurons. In fact,” he adds, “until recently few people believed CB1 was expressed on glutamatergic neurons at all”. “This is an interesting paper in that it clearly shows that endocannabinoid receptors are on glutamatergic neurons as well as GABAergic neurons”, says Yesekiel Ben-Ari (INSERM U29-INMED, Marseilles, France). “However, detailed electrophysiology on these mice is needed to prove that endocannabinoid receptors on hippocampal glutamatergic neurons provide protection against temporal lobe epilepsy.” This fi nding that the endocannabinoid system contributes to the intrinsic defence mechanism of the brain against overexcitation, note Tamas Freund and Istvan Katona (Hungarian Academy of Sciences, Budapest, Hungary), suggests that enhancement of endocannabinoid eff ects might attenuate seizures. Additionally, the animals generated in this study will be extremely useful for unravelling the physiological and pathophysiological function of the endocannabinoid system not only in epilepsy but also in several other neurological diseases.