Abstracts

Rationale: Endocannabinoids and their receptors are recognized as important regulators of neuronal activity. Recently, the potential for cannabidiol (CBD), the major nonpsychoactive component of marijuana, to treat seizures has raised interest in the endocannabinoid system. Attention has focused primarily on CB1 receptors, which are expressed widely throughout the CNS. The role of CB2 receptors in epilepsy has received much less attention; mainly because of their limited expression in the CNS and predominant expression in immune mediators. Recent evidence of CB2 expression in brain, however, raises the possibility of a role in CNS function. Here, we examined CB1/CB2 knockouts for EEG abnormalities. Methods: To determine if the deletion of cannabinoid receptors 1 and 2 affects neuronal activity, three wild-type control and three double cannabinoid receptor KO (CBDKO) mice on a mixed CD1/C57 background were implanted with a single-channel EEG electrode. Animals were 4-5 months of age. Anesthetized mice were implanted bilaterally with electrode leads 1.5 mm lateral to the sagittal suture and 2.7 mm posterior to bregma. Leads were placed just above the dura. EEG and video recordings were conducted within a pathogen-free vivarium barrier facility using a wireless video-EEG telemetry system (DSI). Video-EEG data was blindly reviewed using Neuroscore software to identify seizures and epileptiform activity. EEG events scored as seizures were characterized by the sudden onset of high amplitude (>2X background) activity, signal progression (a change in amplitude and frequency over the course of the event) and a duration greater than ten seconds. Results: Two of three CBDKO mice exhibited handling-induced seizures during cage changes. Behavioral seizures were confirmed by EEG. One of these animals also exhibited multiple spontaneous seizures. Subsequently, all animals were suspended by their tails for 5-10 seconds, which induced seizures in all three CBDKO mice. Additionally, spontaneous and handling-induced behavioral seizures were regularly observed in CBDKO animals not implanted with EEG while maintained in our animal facility. Wildtype animals displayed neither spontaneous nor handling-induced seizures. Conclusions: CB1 KO mice have lowered seizure threshold, but we are not aware of any descriptions of spontaneous seizures. Here, we demonstrated that CB1/CB2 double knockout mice exhibit both spontaneous and handling-induced seizures. Whether the difference reflects a loss of compensatory CB2 expression in CB1 knockouts, or unique effects of CB2 activation remains to be determined. Funding: T-32 ES07051-39 (S.R), DA06668 (NIDA, X.S and S.K.D), R01NS065020 (S.D), R01NS065020 (S.D)