Epileptogenesis following hypoxic ischemic (HI) encephalopathy in the neocortex of a rat model for perinatal HI

Abstract

Little is known of the long-term changes that occur after perinatal hypoxici-schemic insults that lead to epilepsy. Using rats with unilateral carotid occlusion followed by hypoxia at postnatal day 7 (Rice-Vannucci model), this study provides an initial analysis of the epilepsy caused by a perinatal HI insult with chronic and continuous behavioral monitoring, radio-telemetric recording of cortical electroencephalograms (EEG) and in vitro slice electrophysiology. The cortical and hippocampal histopathology were investigated at postnatal day 30 and later at ≥6 months of age using cresyl violet, Timm and rapid Golgi staining and immunocytochemistry. The resultant epilepsy showed an increase in seizure frequency and severity over time with a preponderance for seizure clusters and behavioral features of an ipsilateral cerebral syndrome. The in vitro recording of evoked field potentials (EFPs) in the somatosensory cortices was done at an early and late time point after the initial HI insult. They revealed the progressive nature of the epileptiform activity in the ipsi-lateral spared neocortex that over time spread to involve contralateral mirror cortices. In addition to parasagittal infarcts and porencephalic cysts in severe lesions, columnar neuronal death was found with cytomegaly in isolated groups of dysmorphic cortical neurons. Cortical dysgenesis was seen in the form of deep laminar gliosis, microgyri, white matter hypercellularity, and blurring of the white and grey matter junction. Mossy fiber sprouting was not only detected in the atrophied ipsilateral dorsal hippocampus of HI rats with chronic epilepsy, but was also found in comparable grades in spared ipsi- and contralateral ventral hippocampi. The cortical lesions in this animal model show histological similarities with those found in human perinatal HI. The occurrence of cortical abnormalities that are associated with epilepsy in humans correlates with the subsequent detection of spontaneous recurrent seizures. The accompanying hippocampal reorganization may represent "dual pathology" for the model.