5-Hydroxy Tryptamine Receptor 6 Inactivation Improves Cognitive Impairment in Pilocarpine-Induced Chronic Epilepsy through Modulating Metabolic Injury

5-hydroxy tryptamine 6, a serotonin receptor has been documented to be involved in epilepsy and is exclusively expressed in central nervous system (eg. cerebral cortex, hippocampus, striatum and olfactory tubercle) that mediate cognition. This study attempted to investigate whether 5-hydroxy tryptamine receptor 6 is involved in cognitive impairment of chronic epileptic rats in vivo magnetic resonance imaging study employing a high field (7T) magnet with T2-weighted imaging sequence and magnetic resonance spectroscopy. Rats were divided into control (n=8) and epileptic group (n=37). Status epilepticus was induced by intraperitoneal injection of lithium chloride-pilocarpine. Spontaneous recurrent seizures rats were divided into dimethyl sulfoxide (SE), SB-271046 (SE+SB), WAY-181187 (SE+WAY) group. Spatial learning and memory were evaluated by Morris-water maze test. Hippocampal volumetric analysis was based on T2-weighted coronal images manually calculated regions of interest. Dentate gyrus data were measured to evaluate metabolite ratios to total creatinine by single voxel point resolved spectroscopy-magnetic resonance spectroscopy. After 4 w of SE, spontaneous recurrent seizures were observed and rats showed poor performance in Morris-Maze. SB-271046 intervention attenuated stages and frequency of spontaneous recurrent seizures and improved performance of Morris-Maze. Lac/total creatine(R) and excitatory neurotransmitters (glutamate, combined resonance of glutamate and glutamine, glutamine, taurine) increased significantly in SE group compared to control group. Volumetric analysis showed hippocampal volume decreased significantly and lateral ventricles became larger in SE group. In SE+SB group, score of N-acetyl aspartate/total creatine+choline(R), volume of hippocampus increased significantly, gap between left and right side of N-acetyl aspartate/total creatine+choline, Lac/total creatine(R) glutamate/total creatine(R), combined resonance of glutamate and glutamine/total creatine(R), glutamine/total creatine(R), taurine/total creatine(R) decreased significantly compared to SE group. N-acetyl aspartate/total creatine+choline(R) was positively correlated with time-spent in target quadrant and N-acetyl aspartate/total creatine(L-R) was negatively correlated with time-spent in target quadrant and total swimming distance. In conclusion, lateralization of metabolic injury and over-expression of 5-hydroxy tryptamine receptor 6 are characteristics of pilocarpine-induced chronic epilepsy. SB-271046 can attenuate spontaneous recurrent seizures and improve spatial learning and memory by improving hippocampal metabolic injury.