Neurotoxic damage of granule cells in the dentate gyrus and the cerebellum and cognitive deficit following neonatal administration of phenytoin in mice

Abstract

The use of antiepileptic drugs during human gestation probably increases the risk of causing CNS disorders in later life. In brain, granule cells in the dentate gyrus (DG) and cerebellum are still developing in the last trimester of human gestation and a similar development is taking place during the mouse perinatal period. We treated newborn C57BL/6 mice orally with 35 mg/kg phenytoin (PHT) daily during postnatal days (PD) 5 to 14. Histopathological investigation revealed that the layer of mature granule cells in the DG that was immunoreactive to anti-calbindin D28k was thinner in PHT-treated mice. Purkinje cells in the treated group also had poor, immature arbors with an irregular arrangement. A number of TUNEL-positive cells were observed in the DG and cerebellum during the treatment. PHT-treated mice were impaired in the acquisition of a hidden platform task in the water maze and committed significantly more errors during the learning process in the radial arm maze. These findings demonstrate that neonatal administration of PHT interferes with the development of granule cells in the hippocampus and the cerebellum and causes spatial learning deficits in later life. Cautious clinical use of this drug for pregnant patients is warranted, especially in the last trimester.