Abstracts

Rationale: The focus of clinical studies on human temporal lobe epilepsy (TLE) has recently shifted from the hippocampus to the parahippocampal region due to the fact that changes in excitability and network interactions in the entorhinal cortex may precede the involvement of the hippocampus proper during the development of TLE. We hypothesize that in addition to the perforant pathway, reorganization of other efferent and afferent pathways of the entorhinal cortex may be involved in epileptogenesis. Methods: In the mouse model of TLE at 2 months and 1 year after pilocarpine induced status epilepticus (SE), we aimed to show 1) the cytoarchitectonics of the lateral entorhinal cortex (LEnt) by using cresyl fast violet (CFV) histochemistry and NeuN, calbindin (CB), calretinin (CR) and parvalbumin (PV) immunostaining; 2) reorganization of afferent and efferent pathways by iontophoretical injection of a retrograde tracer cholera toxin B subunit (CTB) or an anterograde tracer phaseolus vulgaris leucoagglutinin (PHA-L) into LEnt; 3) chemical identity of afferent neurons and efferent targets of the LEnt. Results: The main findings include: (1) significant neuronal loss (including both principal cells and CB, CR and PV immunopositive interneurons) occurring in layers II-VI of LEnt at 2 months and 1 year after SE and significant progressive loss of both principal cells and interneurons in layers III-V in the later time point than in the former, (2) in the efferent pathway of the LEnt, more PHA-L labelled en passant and terminal boutons with larger diameter were found not only in the hippocampus and subiculum, but also in the prefrontal cortex, piriform cortex, striatum, perirhinal cortex and amygdaloid complex in SE mice. A unique translaminar distribution and established perisomatic contact with the granule cells and interneurons in the dentate gyrus in SE mice at 1 year was noted. Furthermore, the numbers of CR and CB immunopositive cells contacted by PHA-L labelled en passant and terminal boutons decreased significantly in most of the above areas in SE mice at 2 months or 1 year, and (3) in the afferent pathway of the LEnt, retrogradely labelled cells were reduced significantly in the ipsilateral the piriform cortex and endopiriform nucleus in SE mice at the two time points, and in the reuniens thalamic nucleus in SE mice at 1 year. The percentage of the number of CTB and CB, CR double-labelled neurons to all the retrogradely labelled neurons was significantly decreased in the reunions thalamic nucleus in SE mice at 1 year.Conclusions: The cytoarchitectonic change of the LEnt has led to extensive reorganization of its efferent and afferent pathways. While our previous neuroanatomical and neurophysiological studies do not strongly support the roles perforant pathway plays in the occurrence of spontaneously recurrent seizures, reorganization of other efferent and afferent pathways of the LEnt may be related to seizure initiation, generation, and propagation to the motor cortex in either a direct or indirect way.