Temporal characterization of changes in hippocampal cannabinoid CB 1 receptor expression following pilocarpine-induced status epilepticus

Abstract

Several reports have focused on the involvement of the endocannabinoid system in hyperexcitability, particularly in seizure and epilepsy models. Our laboratory recently characterized a novel plasticity change of the cannabinoid type 1 (CB 1) receptor in hippocampi of epileptic rats following pilocarpine-induced status epilepticus (SE). This long-term redistribution included selective layer-specific changes in CB 1 receptor expression within distinct hippocampal subregions. However, the temporal characteristics of this redistribution during the development of epilepsy had not been examined. Therefore, this study was initiated to evaluate the time course by which pilocarpine-induced SE produced changes in CB 1 receptor expression. Immunohistochemical analysis demonstrated that within 1 week following SE, there was a pronounced loss in CB 1 receptor expression throughout the hippocampus, while staining in many interneurons was preserved. By 1 month post-SE, pilocarpine-treated animals began to display epileptic seizures, and CB 1 receptor expression was characteristic of the redistribution observed in long-term epileptic rats, with decreases in CB 1 receptor immunoreactivity in the stratum pyramidale neuropil and dentate gyrus inner molecular layer, and increases in the strata oriens and radiatum of CA1–3. Observed changes in CB 1 receptor expression were confirmed at multiple time points by western blot analysis. The data indicate that overall decreases in expression following SE preempt a long-lasting CB 1 receptor redistribution, and that differential responses occur within the hippocampus to initial CB 1 receptor losses. This suggests a role for dysregulation of the endocannabinoid system during epileptogenesis and indicates that the CB 1 receptor redistribution temporally correlates with the emergence of epileptic seizures.