Correlated ultrastructural damage between cerebellum cells after early anticonvulsant treatment in mice

The anticonvulsants phenobarbital and diphenylhydantoin administered early in life to mice resulted in significant and long-lasting ultrastructural damage, including abnormalities of mitochondria, myelin sheaths, and lamellar inclusion bodies inside identified cells throughout the cortical layers of the cerebellum in treated vs control mice. The magnitude, distribution and duration of damage was age and treatment specific. No differences were detected in density of parallel fiber processes nor in synapse density within the molecular layer. Neuron profiles containing damaged organelles were not homogeneously distributed but made up only a small fraction of the total cell population examined. In our experiments, there was an overall within-animal correlation explaining 45% of the magnitude of damage in different cerebellar regions, but between synaptically connected cells, specifically mossy fiber axon varicosities and granule cell dendrite profiles, the subset population ratio of damaged-to-total mitochondria was highly significantly correlated (70-90%; P less than 0.001). We hypothesized that some correlated transneuronal degeneration and death in the central nervous system may have a transynaptically regulated component that first appears as correlated damage between synaptically connected cells, perhaps regardless of the degree of toxicity. The orderly cytoarchitecture and cell connections of the cerebellar cortex can be used to study these patterns of degeneration.