Endocannabinoids target glutamatergic neurons to protect against seizures

Monory K et al. (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51: 455–466

The endocannabinoid system is known to play an important role in the control of neuronal excitability through its modulatory effects on γ-aminobutyric acid (GABA)-releasing neurons and glutamatergic neurons. Monory et al. investigated the mechanism by which the system exerts this function on glutamatergic neurons. Their findings indicate that glutamatergic neurons located in the hippocampus are directly targeted by endocannabinoids via CB₁ receptors located on glutamatergic terminals.

Using mice in which cannabinoid receptor genes could be deleted in specific cell populations, the authors carried out a series of experiments to examine the role of the endocannabinoid system in the hippocampus during kainic-acid-induced seizures. They developed a mouse strain (Glu-CB₁^−/−) in which the cannabinoid CB₁ receptor was selectively deleted in cortical glutamatergic neurons located in the hippocampus, neocortex and amygdala, while its expression was maintained in GABAergic interneurons and subcortical neurons.

Seizures evoked in Glu-CB₁^−/− mice were found to be stronger than those evoked in wild-type littermates or other mutant mice in which the deletion of CB₁ receptors was specifically limited to GABAergic neurons, thus demonstrating that CB₁ receptors located on cortical glutamatergic neurons play an essential role in protecting these neurons against kainic-acid-induced seizures.

The authors conclude that their results indicate a mechanism through which the endocannabinoid system directly protects the brain against epileptiform seizures in an 'on-demand' manner. They suggest that the CB₁ receptor on hippocampal glutamatergic neurons represents a novel potential target for pharmacological interventions against abnormal neuronal excitation.