Abstracts

An imbalance between excitatory and inhibitory synaptic transmission is believed to be a primary mechanism underlying seizure discharge. Endocannabinoids in the brain have been shown to operate as retrograde modulators of inhibitory and excitatory neuronal transmission through activation of the presynaptic cannabinoid type-1 receptor (CB1). Studies from our laboratory have shown that exogenous cannabinoids infer CB1-dependent anticonvulsant activity in both in vivo and in vitro models of seizure and epilepsy (Blair et al., 2006, JPET, 317(3),1072-78; Wallace et al., 2003, JPET, 307(1), 129-37), and that the endocannabinoid system acts to tonically regulate epileptic seizure discharge through CB1 activation. Furthermore, we have observed a permanent redistribution of CB1 protein expression throughout the hippocampal formation in the rat pilocarpine-induced status epilepticus (SE) model of acquired epilepsy. This study was carried out to determine if the reorganization of the CB1 in the epileptic hippocampus acts to redirect the role of the endocannabinoid system towards regulating excitatory and inhibitory synaptic transmission., The rat pilocarpine-induced SE model of acquired epilepsy was utilized for this study. Epileptic and control animals were anesthetized and the brains were perfusion-fixed transcardially. Brain cryosections were made and processed for immunofluorescent co-localization analysis using antibodies specific for the CB1 and markers for excitatory (vesicular glutamate transporter 1: VGLUT1) and inhibitory (vesicular GABA transporter: VGAT) terminals., When compared to control, CB1 immunostaining was increased in epileptic hippocampus in the stratum oriens and radiatum throughout the CA1-CA3 molecular regions that co-localized with VGLUT1-positive glutamatergic terminals. In the CA1-CA2 stratum pyramidale layer highly enriched with VGAT-positive GABAergic terminals, CB1 immunostaining was dramatically decreased in epileptic hippocampus as compared to controls., These findings demonstrate that pilocarpine-induced SE, with subsequent development of epilepsy, causes a redistribution of CB1 expression as indicated by both an increase at glutamatergic and decrease at GABAergic terminals. Such a reorganization of the CB1-dependent endocannabinoid pathway throughout the hippocampus would act to suppress excitatory and increase inhibitory synaptic transmission in the epileptic phenotype and may underlie the anticonvulsant properties of cannabinoids in this model., (Supported by RO1-NS23350, P50-NS25630, and NIDA (DA05274, DA07027,DA11322).)