Remodeling of neuronal circuitries in human temporal lobe epilepsy: Increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex

Neuronal loss and axonal sprouting are the most typical histopathological f indings in the hippocampus of patients with drug-refractory temporal lobe e pilepsy (TLE). It is under dispute, however, whether remodeling of neuronal circuits is a continuous process or whether it occurs only during epilepto genesis. Also, little is known about the plasticity outside of the hippocam pus. We investigated the immunoreactivity of the highly polysialylated neur al cell adhesion molecule (PSA-NCAM) in the surgically removed hippocampus and the entorhinal cortex of patients with drug-refractory TLE (n = 25) and autopsy controls (n = 7). Previous studies have shown that the expression of PSA-NCAM is associated with the induction of synaptic plasticity, neurit e outgrowth, neuronal migration, and events requiring remodeling or repair of tissue. In patients with TLE, the optical density (OD) of punctate PSA-N CAM immunoreactivity was increased both in the inner and outer molecular la yers of the dentate gyrus, compared with controls. The intensity of PSA-NCA M immunoreactivity in the inner molecular layer correlated with the duratio n of epilepsy, severity of hippocampal neuronal loss, density of mossy fibe r sprouting, and astrogliosis. In TLE patients with only mild neuronal loss in the hippocampus, the density of intragranular immunopositive neurons wa s increased twofold compared with controls, whereas in TLE patients with se vere neuronal lass, the infragranular PSA-NCAM-positive cells were not pres ent. In the hilus, the somata and tortuous dendrites of some surviving neur ons were intensely stained in TLE. PSA-NCAM immunoreactivity was also incre ased in CA1 and in layer II of the rostral entorhinal cortex, where immunop ositive neurons were surrounded by PSA-NCAM-positive fibers and puncta Our data provide evidence that synaptic reorganization is an active process in human drug-refractory TLE. Moreover, remodeling is not limited to the denta te gyrus, but also occurs in the CA1 subfield and the entorhinal cortex.