Altered serotonin innervation in the rat epileptic brain

Studies in animal models of epilepsy revealed compromised serotonin (5-HT) transmission between the raphe nuclei and the brain limbic system. The goal of the present study was to evaluate the effects of epilepsy on the structural integrity of the dorsal (DR) and median (MnR) raphe nuclei and on the morphology of serotonergic fiber terminals in the dentate gyrus (DG), infralimbic cortex (IL) and medial septum (MS). The study was performed in adult Wistar rats using the kainate (9.5 mg/kg) status epilepticus (SE) model. Four months post-SE, the brainstem sections of the animals were immunostained for 5-HT, whereas the forebrain sections were immunostained for serotonin transporter (SERT). Stereological analysis revealed that epileptic rats, as compared to controls, had approximately 30% less 5-HT-stained cells in the interfascicular part of the DR, but twice as many 5-HT-stained cells in the MnR. Another finding was the reorganization of the 5-HT fiber network in all target areas analyzed, as indicated by the rightward shift of the density-size distribution histograms of SERT-stained fiber varicosities. Nonlinear regression analysis of these histograms revealed that SERT-stained varicosities were represented by two subpopulations characterized by distinct cross-sectional areas. The areal density of the small-sized varicosities was decreased in the DG (hilus and molecular layer), IL cortex (layers II/III) and MS, while that of the larger-sized varicosities was increased. The present results support the hypothesis that chronic epilepsy can trigger profound structural reorganization of the ascending serotonergic pathways in the rat brain.