Neurobiological studies of experimental diphenylhydantoin intoxication. - I. Electron microscopic investigations of the rat cerebellum with chronic diphenylhydantoin intoxication.

The effect of chronic administration of diphenylhydantoin on the fine structures of the rat cerebellum was ultrastructurally investigated. Materials from nine control rats and 16 experimental rats to which 200 to 300 mg/kg b.wt. of diphenylhydantoin was administered orally for 12 months were studied with the light and electron microscopes. The most striking changes were observed in the presynaptic boutons located predominantly in the molecular layer and the neuropil of deep cerebellar nuclei and sometimes in the granule cell layer. The changes consisted of the proliferation of either interconnected tubules 150 to 350 A in diameter associated with membranous scrolls and/or membranous strands separated by a cleft-like space, or parallel tubules about 600 A in diameter with a honeycomb-like architecture in the cross section, and hypertrophy of the boutons. Other alterations were a generalized increase in the density of the axoplasmic matrix, the accumulation of mitochondria, vesicular structures and dense bodies, an increased number of neurofilaments and a decreased number of synaptic vesicles. The axon displayed morphological abnormalities similar to those found in the terminal boutons. Along with the synaptic and axonic changes mentioned above, the perikaryal alterations in the Purkinje cell and in granule cell layers and deep cerebellar nuclei were also found, but they were generally not so prominent so that they were considered to reflect a non-specific reaction to synapto-axonic changes rather than a primary degenerative change. However, in contrast to the neuronal changes, no indication of damage of the glial elements was found, nor were the vascular changes.