Hereditary Neuronal Microdysgenesis and Acquired Lesions in the Hippocampal Formation of Ihara Epileptic Rat
Authors: Tsiiji Atsushi , Amano Shigeru , Yokoyama Masao , Fukuoka Junya , Sasaharii Masakiyo , Ihara Nobuo , Hazama Fumitada , Matsuds Masayuki 
Published: August 2005

Purpose: Ccrebral dysplasia including neuronal microdysgcnesis is reported in a large series or cortical resections obtained from patients with medically intractable epilepsy, Some investigators believe that the cerebral dysplasia is linked intiinatcly to epileptogcnesis and seizurepropagation. The Ihara Epileptic Rat (IER), previously tcrmed Ihara's genetically epilcptic rat (IGER), is a novel rat mutant with limbic‐like seizures. Hyperactivity with wild running, jumping, kicking, or wet‐ dog shaking appear at approximately 2 months after birth. Abnormal circling seizures begin approximately 3 months after hirth, and the rats repeatcdly rotate, as if chasing their tails. Spontaneous generalized tonic‐chic convulsions become evident approximately 5–6 months after birth. The frequency of the generalized convulsions usually is no more than I attack per week initially, but with aging thc convulsions become more frequent. Seizure forms present i n I of 3 patterns: abnormal behavior, circling seizures, and generalized tonic‐clonic coilvulsions, which can be documented by automatic seimre monitoring systems. Neuropathological findings in the hippocampus or IER include cctopic cell clusters consisting of neurons in the region of the Ftratum radiatum, disorientation oi pyramidal neuron alignment. a “wavy” granule cell layer, and enlargement of the hippocampal formation. It is assumed that the changes in the hippocampus consist of hereditary lesions and acquired lesions. The aim of the present study was to distinguish the hereditary hippocampal lesions from the acquired lesion in the IER model.

Methods: Two month‐old IERs without apparent abnormal behavior, and twelve month‐old IERs with abnormal behaviors, abnormal circling seizures, or generalized tonic‐clonic convulsions (5 males and 5 fernales pel‐ group) were used for neuropiithological investigation. Agematchcd Wistar rats were used as controls. Anesthetized rats were pcrlused with 4% formaldehyde injected into the heart, and the brains then wcrc removed. Frozen brains were serially sliced 30 pm with a frozcii inicrotome and thc slices stained with Cresyl violet acetate, Nissl staining. Histopathological studies were performcd i n order to examine the hippocampal lesions, the features, the localization, and the sevcrity. Semiquantitativc analysis lor these lesions was also carried out.

Results: Ectopic neuronal clusters i n the region of the stratum EIdiatum on the border of stratum lacunosum moleculare in the CAI of the anterior dorsal hippocampus occurred without exception in male and fcmale 2 and 12 month‐old IER. Disarray of pyramidal neurons or sinall foci of ncuronal interruption in the zonal structure of the pyra‐ midal ccll layer was also found, almost always in the CAI and sometimes in the CA3 regions. These lesions, neuronal clusters, and disorientation of pyramidal neurons were coininoii findings in all IER examined. Conversely, the wavy forin of the dentate gyrus and enlargement of the hippocainpal formation, which occurred in thc I2 month‐old rats, showed differences iii the severity among the groups of IER. Thc degree of wavy form or enlargement of hippocampal forniation dcpcndcd on the degree of thc seizure activities. The degree of lesions was more scvcre in the hippocampus in rats with more severe seizure activitics. A mild degree of wavy forin in the granule cell layer, but no enlargement of hippocampal formation, was found in 2‐month old IER. No ectopic neuronal clusters, disarrangement of pyramidal neurons in the hippocainpal formation, wavy form of the granule cell layer, or enlargcmcnt of hippocampus wcre found in any control rats.

Conclusions: This study dcmonstrates that the ectopic neuronal clusind disarray of the pyramidal neurons arc hereditary lesions, such as programmed neuronal microdysgenesis. Thc wavy form of the dcntare granule ccll and enlargement of thc hippocampal formation, on the consequence of epileptic activities.